Compounds capable of activating cholinergic receptors

ABSTRACT

The present invention generally relates to nicotinic compounds, in the form of aryl substituted olefinic compounds, as well as pro-drug, N-oxide, metabolite and pharmaceutically acceptable salt forms thereof. Methods of modulating neurotransmitter release via administration of the compounds, pro-drugs, N-oxides and/or pharmaceutically acceptable salts are also disclosed.

CROSS REFERENCE TO RELATED APPLICATIONS

This is a continuation-in-part application claiming benefit of Appln.No. 09/973,411 filed Oct. 9, 2001, pending, itself a continuationapplication claiming the benefit of Appln. No. 09/641,496 filed Aug. 18,2000, abandoned, itself a continuation application claiming the benefitof Appln. No. 09/522,117 filed Mar. 9, 2000, pending, itself acontinuation application claiming the benefit of Appln. No. 09/098,285filed Jun. 16, 1998, abandoned; and claiming benefit as acontinuation-in-part application of Appln. No. 08/631,761 filed Apr. 23,1996, now abandoned.

TECHNICAL FIELD

The present invention relates to generally to nicotinic compounds. Morespecifically, the present invention relates to compounds that, whenadministered and, optionally, metabolized, are capable of activatingnicotinic cholinergic receptors, for example, as agonists of specificnicotinic receptor subtypes.

BACKGROUND

Nicotine has been proposed to have a number of pharmacological effects.See, for example, Pullan et al. N. Engl. J. Med. 330:811-815 (1994).Certain of those effects may be related to effects upon neurotransmitterrelease. See for example, Sjak-shie et al., Brain Res. 624:295 (1993),where neuroprotective effects of nicotine are proposed. Release ofacetylcholine and dopamine by neurons upon administration of nicotinehas been reported by Rowell et al., J. Neurochem. 43:1593 (1984); Rapieret al., J. Neurochem. 50:1123 (1988); Sandor et al., Brain Res. 567:313(1991) and Vizi, Br. J. Pharmacol. 47:765 (1973). Release ofnorepinephrine by neurons upon administration of nicotine has beenreported by Hall et al., Biochem. Pharmacol. 21:1829 (1972). Release ofserotonin by neurons upon administration of nicotine has been reportedby Hery et al., Arch. Int. Pharmacodyn. Ther. 296:91 (1977). Release ofglutamate by neurons upon administration of nicotine has been reportedby Toth et al., Neurochem Res. 17:265 (1992). In addition, nicotinereportedly potentiates the pharmacological behavior of certainpharmaceutical compositions used for the treatment of certain disorders.See, Sanberg et al., Pharmacol. Biochem. & Behavior 46:303 (1993);Harsing et al., J. Neurochem. 59:48 (1993) and Hughes, Proceedings fromIntl. Symp. Nic. S40 (1994). Furthermore, various other beneficialpharmacological effects of nicotine have been proposed. See, Decina etal., Biol. Psychiatry 28:502 (1990); Wagner et al., Pharmacopsychiatry21:301 (1988); Pomerleau et al., Addictive Behaviors 9:265 (1984);Onaivi et al., Life Sci. 54(3):193 (1994); Tripathi et al., JPET 221:91-96 (1982) and Hamon, Trends in Pharmacol. Res. 15:36.

Various nicotinic compounds have been reported as being useful fortreating a wide variety of conditions and disorders. See, for example,Williams et al. DN&P 7(4):205-227 (1994), Arneric et al., CNS Drug Rev.1(1):1-26 (1995), Arneric et al. Exp. Opin. Invest. Drugs 5(1):79-100(1996), Bencherif et al., JPET 279:1413 (1996), Lippiello et al., JPET279:1422 (1996), Damaj et al., Neuroscience (1997), Holladay et al., J.Med. Chem. 40(28): 4169-4194 (1997), Bannon et al., Science 279: 77-80(1998), PCT WO 94/08992, PCT WO 96/31475, and U.S. Pat. Nos. 5,583,140to Bencherif et al., 5,597,919 to Dull et al., 5,604,231 to Smith et al.and 5,616,716 to Dull et al. Nicotinic compounds are reported as beingparticularly useful for treating a wide variety of Central NervousSystem (CNS) disorders.

CNS disorders are a category of neurological disorders that can arisefrom genetic predispositions or environmental factors, such asinfection, trauma, and drug use. In some instances, the etiology ofparticular CNS disorders is unknown. CNS disorders compriseneuropsychiatric disorders, neurological diseases and mental illnesses;and include neurodegenerative diseases, behavioral disorders, cognitivedisorders and cognitive affective disorders. There are several CNSdisorders whose clinical manifestations have been attributed to CNSdysfunction (i.e., disorders resulting from inappropriate levels ofneurotransmitter release, inappropriate properties of neurotransmitterreceptors, and/or inappropriate interaction between neurotransmittersand neurotransmitter receptors). Several CNS disorders can be attributedto cholinergic, dopaminergic, adrenergic and/or serotonergicdeficiencies. CNS disorders of relatively common occurrence includepresenile dementia (early onset Alzheimer's disease), senile dementia(dementia of the Alzheimer's type), Lewy Body dementia, Parkinsonismincluding Parkinson's disease, Huntington's chorea, tardive dyskinesia,hyperkinesia, mania, attention deficit disorder, anxiety, dyslexia,schizophrenia, mile cognitive impairment and Tourette's syndrome.

It, therefore, is desirable to provide a useful method for theprevention and treatment of a condition or disorder by administering anicotinic compound to a subject susceptible to or suffering from such amalady. It is highly beneficial to provide individuals suffering fromcertain disorders (e.g., CNS disorders) with interruption or reductionin the severity of the symptoms of those disorders by the administrationof a pharmaceutical composition that contains an active ingredient or apro-drug form or an N-oxide having nicotinic pharmacology. It is alsodesirable to provide a pharmaceutical composition incorporating acompound that when administered and metabolized interacts with nicotinicreceptors, such as those which have the potential to affect thefunctioning of the central nervous system (CNS), but that when employedin an amount sufficient to affect the functioning of the central nervoussystem (CNS), does not significantly affect those receptor subtypes thathave the potential to induce undesirable side effects (e.g., appreciableactivity at skeletal muscle and ganglia sites).

SUMMARY

The present invention generally relates to nicotinic compounds, as wellas pro-drug, N-oxide, metabolite and pharmaceutically acceptable saltforms thereof. The present invention encompasses nicotinic compounds,such as aryl substituted olefinic amines. Representative arylsubstituted olefinic amines include(4E)-N-methyl-5-(3-pyridyl)-4-penten-2-amine,(4E)-N-methyl-5-(5-pyrimidinyl)-4-penten-2-amine,(4E)-N-methyl-5-(5-methoxy-3-pyridyl)-4-penten-2-amine,(4E)-N-methyl-5-(6-amino-5-methyl-3-pyridyl)-4-penten-2-amine,(2R)-(4E)-N-methyl-5-(3-pyridyl)-4-penten-2-amine,(2R)-(4E)-N-methyl-5-(5-isopropoxy-3-pyridyl)-4-penten-2-amine,(4E)-N-methyl-5-(5-bromo-3-pyridyl)-4-penten-2-amine,(4E)-N-methyl-5-(5-ethoxy-3-pyridyl)-4-penten-2-amine,(2S)-(4E)-N-methyl-5-(3-pyridyl)-4-penten-2-amine,(4E)-N-methyl-5-(5-isopropoxy-3-pyridyl)-4-penten-2-amine and(2S)-(4E)-N-methyl-5-(5-isopropoxy-3-pyridyl)-4-penten-2-amine. Thepresent invention also relates to methods for synthesizing arylsubstituted olefinic amine compounds, such as the compounds of thepresent invention. For example, methods of synthesizing isolatedenantiomeric forms of aryl substituted olefinic compounds are providedby the present invention.

The present invention also encompasses pro-drug forms of nicotiniccompounds. The pro-drug forms can include, for example, amide,thioamide, carbamate, thiocarbamate, urea and thiourea forms of arylsubstituted olefinic amine compounds of the present invention.

The present invention also provides methods of making and using pro-drugforms of nicotinic compounds, such as aryl substituted olefinic amines.The methods of making pro-drugs include, among others, acylation andalkylation of nicotinic compounds, such as aryl substituted olefinicamines.

The present invention also encompasses metabolite forms of nicotiniccompounds and methods of making such metabolites. The metabolites caninclude, among others, N-de-alkylated and monohydroxy and dihydroxyforms of the aryl substituted olefinic amines described herein, whereinthe mono- or di-hydroxy functionality is present on the pyridine orpyrimidine rings. The present invention also encompasses N-oxide formsof aryl substituted olefinic amine compounds and methods of making andusing such N-oxide forms.

The present invention also relates to methods of modulating or alteringthe activity of a receptor by administering an effective amount of acompound, a pro-drug, an N-oxide and/or a salt of the present inventionto a subject. The methods can include modulating the activity of anicotinic cholinergic receptor by contacting the receptor with aneffective amount of a compound of the present invention.

The present invention also relates to methods for the prevention and/ortreatment of a wide variety of conditions or disorders, and particularlythose disorders characterized by dysfunction of nicotinic cholinergicneurotransmission including disorders involving neuromodulation ofneurotransmitter release, such as dopamine release. The presentinvention also relates to methods for the prevention and/or treatment ofdisorders, and/or their symptoms such as central nervous system (CNS)disorders, which are characterized by an alteration in normalneurotransmitter release.

The present invention also encompasses methods for the treatment ofcertain conditions, such as, for example, pain and the symptomsassociated therewith. The methods involve administering to a subject aneffective amount of a compound of the present invention and/or apro-drug, N-oxide, and/or salt form thereof.

The present invention, in another aspect, relates to pharmaceuticalcompositions comprising effective amounts of a compound of the presentinvention and/or a pro-drug, N-oxide, and/or salt from thereof. Suchpharmaceutical compositions incorporate compounds that, when employed ineffective amounts, can interact with relevant nicotinic receptor sitesof a subject, thereby allowing the compound to act as a therapeuticagent in the prevention or treatment of a wide variety of conditions anddisorders and/or symptoms thereof, particularly those disorderscharacterized by an alteration in normal neurotransmitter release.Preferred pharmaceutical compositions comprise compounds of the presentinvention and/or pro-drugs, N-oxides, metabolites and/or pharmaceuticalsalts thereof.

The pharmaceutical compositions of the present invention are useful forthe prevention and/or treatment of disorders, such as CNS disorders,which are characterized by an alteration in normal neurotransmitterrelease, and/or symptoms associated with such disorders. Thepharmaceutical compositions provide therapeutic benefit to individualssuffering from such disorders and/or exhibiting clinical manifestationsof such disorders in that the compounds within those compositions, whenemployed in effective amounts, have the potential to (i) exhibitnicotinic pharmacology and affect relevant nicotinic receptors sites(e.g., act as a pharmacological agonist to activate nicotinicreceptors), and (ii) elicit neurotransmitter secretion, and henceprevent and suppress the symptoms associated with those diseases. Inaddition, the compounds can (i) increase the number of nicotiniccholinergic receptors of the brain of the patient, (ii) exhibitneuroprotective effects and (iii) when employed in effective amounts donot cause appreciable adverse side effects (e.g., significant increasesin blood pressure and heart rate, significant negative effects upon thegastro-intestinal tract, and significant effects upon skeletal muscle).The pharmaceutical compositions of the present invention are believed tobe safe and effective with regards to prevention and treatment of a widevariety of conditions and disorders.

The foregoing and other aspects of the present invention are explainedin detail in the detailed description and examples set forth below.

DETAILED DESCRIPTION

As used herein, the term “pro-drug” refers to a pharmacologicallyinactive form of a compound that undergoes biotransformation prior toexhibiting its pharmacological effect(s). A pro-drug is one that ismetabolized in vivo by a subject after administration into apharmacologically active form of the compound in order to produce thedesired pharmacological effect. After administration to the subject, thepharmacologically inactive form of the compound is converted in vivounder the influence of biological fluids and/or enzymes into apharmacologically active form of the compound. Although metabolismoccurs for many compounds primarily in the liver and/or kidney, almostall other tissues and organs, especially the lung, are able to carry outvarying degrees of metabolism. Pro-drug forms of compounds can beutilized, for example, to improve bioavailability, mask unpleasantcharacteristics such as bitter taste, alter solubility for intravenoususe, or to provide site-specific delivery of the compound. Reference toa compound herein includes pro-drug forms of a compound.

As used herein, “metabolite” refers to a form of a compound that is theproduct of that compound after undergoing a biologically inducedtransformation. A metabolite can be produced synthetically.

As used herein, “N-oxide” refers to an N-oxide form of a compoundwherein one or several nitrogen atoms are oxidized to the so-calledN-oxide.

As usual herein, “pharmaceutically acceptable salt” refers to a saltform of a compound that has found acceptance in the pharmaceuticalindustry.

The compounds of the present invention include compounds of the formula:

and pharmaceutically acceptable salts thereof,

where each of X and X′ is individually nitrogen or carbon bonded to asubstituent species characterized as having a sigma m value in the rangeof about −0.3 to about 0.75; as determined in accordance with Hansch etal., Chem. Rev. 91:165 (1991). As shown in the formula, m is an integerand n is an integer such that the sum of m plus n is 1, 2, 3, 4, 5, 6,7, or 8. In one embodiment, the sum of m plus n is 1, 2 or 3. Whereas,in another embodiment, the sum of m and n is 2 or 3. The wavy line inthe formula indicates that the compound can have the cis (Z) or trans(E) form. E^(I), E^(II), E^(III), E^(IV), E^(V) and E^(VI) individuallyrepresent hydrogen or lower alkyl (e.g., straight chain or branchedalkyl including C₁-C₈, for example, C₁-C₅, such as methyl, ethyl, orisopropyl) or halo substituted lower alkyl (e.g., straight chain orbranched alkyl including C₁-C₈, for example, C₁-C₅, such astrifluoromethyl or trichloromethyl), and at least one of E^(I), E^(II),E^(III), E^(IV), E^(V) and E^(VI) is non-hydrogen. Preferably, E^(V)and/or E^(VI) is a C₁₋₅ alkyl, more preferably, methyl. Z′ and Z″individually represent hydrogen or lower alkyl (e.g., straight chain orbranched alkyl including C₁-C₈, for example C₁-C₅, such as methyl,ethyl, or isopropyl). In one embodiment, one of Z′ and Z″ is hydrogen.In another embodiment, Z′ is hydrogen and Z″ is methyl. Alternatively,Z′ is hydrogen and Z″ represents a ring structure (cycloalkyl oraromatic), such as, for example, cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl, adamantyl, quinuclidinyl, pyridyl, quinolinyl,pyrimidinyl, phenyl, benzyl (where any of the foregoing can be suitablysubstituted with at least one substituent group, including thosesubstituent groups described below with respect to X and X′, andparticularly include alkyl, halo, and amino substituents). In addition,Z′, Z″, and the associated nitrogen atom alternatively can form a ringstructure, such as aziridinyl, azetidinyl, pyrollidinyl, piperidinyl,quinuclidinyl, piperazinyl, or morpholinyl.

Furthermore, one of Z′ and Z″ can be —C(═Q) Q′, where Q is O, S or NR′and Q′ is OR′, SR′, N(R′)₂ or R′, where R′ is as defined below. Morespecifically, one of Z′ and Z″ can be CH₃C(═O)—, —C(═O)OC₆H₅,—C(═O)N(CH₃)₂, —C(═S)CH₂CH₃, —C(═S)NH₂, —C(═S)N(CH₃)₂, —C(═S)OCH₃, or—C(═O)C₆H₅.

More specifically, X and X′ individually can be N, NO, C—H, C—F, C—Cl,C—Br, C—I, C—R′, C—NR′R″, C—CF₃, C—OH, C—CN, C—NO₂, C—C₂R′, C—SH,C—SCH₃, C—N₃, C—SO₂CH₃, C—OR′, C—SR′, C—C(═O)NR′R″, C—NR′C(═O)R′,C—C(═O)R′, C—C(═O)OR′, C(CH₂)_(q)OR′, C—OC(═O)R′, COC(═O)NR′R″ andC—NR′C(═O)OR′ where R′ and R″ are individually hydrogen or lower alkyl(e.g., C₁-C₁₀ alkyl, for example, C₁-C₅ alkyl, such as methyl, ethyl,isopropyl or isobutyl), an aromatic group-containing species or asubstituted aromatic group-containing species, and q is an integer from1 to 6. R′ and R″ can be straight chain or branched alkyl, or R′ and R″can form a cycloalkyl functionality (e.g., cyclopropyl cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, and quinuclidinyl).Representative aromatic group-containing species include pyridyl,quinolinyl, pyrimidinyl, phenyl, and benzyl (where any of the foregoingcan be suitably substituted with at least one substituent group, such asalkyl, halo, or amino substituents). Other representative aromatic ringsystems are set forth in Gibson et al., J. Med. Chem. 39:4065 (1996).When X and X′ represent a carbon atom bonded to a substituent species,that substituent species can have a sigma m value in the range of about−0.3 to about 0.75, preferably in the range of about −0.25 to about0.60. In certain circumstances the substituent species is characterizedas having a sigma m value not equal to 0. A, A′ and A″ individuallyrepresent those species described as substituent species to the aromaticcarbon atom previously described for X and X′; and can include hydrogen,halo (e.g., F, Cl, Br, or I), alkyl (e.g., lower straight chain orbranched C₁₋₈ alkyl, such as methyl or ethyl), OR′ or N(R′R″), whereinR′ and R″ are defined as above. Furthermore, A, A′ and A″ individuallycan be OH. In one embodiment, both A and A′ are hydrogen. In otherembodiments, A and A′ are hydrogen, and A″ is hydroxy, halo, amino,methyl or ethyl. In yet other embodiments, A, A′ and A″ are allhydrogen. In one embodiment, m is 1 or 2, n is 1, E^(I), E^(II),E^(III), E^(IV) and E^(VI) each are hydrogen, and E^(V) is alkyl (e.g.,methyl).

Depending upon the identity and positioning of each individual E^(I),E^(II), E^(III), E^(IV), E^(V) and E^(VI), certain compounds can beoptically active. Additionally, compounds of the present invention canhave chiral centers within the alkenyl side chain (e.g., the compoundcan have an R or S configuration depending on the selection of E^(III),E^(IV), E^(V) and E^(VI), with the S configuration being at least oneembodiment). Depending upon E^(I), E^(II), E^(III), E^(IV), E^(V) andE^(VI), compounds of the present invention have chiral centers, and thepresent invention relates to racemic mixtures of such compounds as wellas enantiomeric compounds. Typically, the selection of m, n, E^(I),E^(II), E^(III), E^(IV), E^(V) and E^(VI) is such that up to about 4,and frequently up to 3, and usually 1 or 2, of the substituentsdesignated as E^(I), E^(II), E^(III), E^(IV), E^(V) and E^(VI) arenon-hydrogen substituents (i.e., substituents such as lower alkyl orhalo-substituted lower alkyl). Typically, X is CH, CBr or COR′. In thepreferred embodiment, X′ is nitrogen.

The present invention also encompasses compounds of the formula:

and pharmaceutically acceptable salts thereof,

where m, E^(I), E^(II), E^(III), E^(IV), X, Z′, Z″, A, A′ and A″ are asdefined hereinbefore.

Representative compounds of the present invention are (3E) and(3Z)-N-methyl-4-(3-pyridyl)-2-methyl-3-buten-1-amine, (3E) and(3Z)-N-methyl-4-(3-pyridyl)-3-methyl-3-buten-1-amine, (5E) and(5Z)-N-methyl-6-(3-pyridyl)-5-hexen-3-amine, (4E) and(4Z)-N-methyl-5-(3-pyridyl)-2-methyl-4-penten-2-amine, (4E) and(4Z)-N-methyl-5-(3-pyridyl)-3-methyl-4-penten-2-amine, (4E) and(4Z)-N-methyl-5-(3-pyridyl)-4-penten-2-amine, (4E) and(4Z)-N-methyl-5-(3-pyridyl)-1,1,1-trifluoro-4-penten-2-amine, (4E) and(4Z)-N-methyl-5-(3-pyridyl)-4-methyl-4-penten-1-amine, (4E) and(4Z)-N-methyl-5-(3-pyridyl)-4-methyl-4-penten-2-amine, (1E) and(1Z)-N-methyl-1-(3-pyridyl)-1-octen-4-amine, (1E) and(1Z)-N-methyl-1-(3-pyridyl)-5-methyl-1-hepten-4-amine, (5E) and(5Z)-N-methyl-6-(3-pyridyl)-5-methyl-5-hexen-2-amine, (5E) and(5Z)-N-methyl-6-(3-pyridyl)-5-hexen-2-amine, (5E) and(5Z)-N-methyl-6-(3-pyridyl)-5-methyl-5-hexen-3-amine, (3E) and(3Z)-4-(3-pyridyl)-2-methyl-3-buten-1-amine, (3E) and(3Z)-4-(3-pyridyl)-3-methyl-3-buten-1-amine, (5E) and(5Z)-6-(3-pyridyl)-5-hexen-3-amine, (4E) and(4Z)-5-(3-pyridyl)-2-methyl-4-penten-2-amine, (4E) and(4Z)-5-(3-pyridyl)-3-methyl-4-penten-2-amine, (4E) and(4Z)-5-(3-pyridyl)-4-penten-2-amine, (4E) and(4Z)-5-(3-pyridyl)-1,1,1-trifluoro-4-penten-2-amine, (4E) and(4Z)-5-(3-pyridyl)-4-methyl-4-penten-1-amine, (4E) and(4Z)-5-(3-pyridyl)-4-methyl-4-penten-2-amine, (1E) and(1Z)-1-(3-pyridyl)-1-octen-4-amine, (5E) and(5Z)-6-(3-pyridyl)-5-methyl-5-hexen-2-amine, (5E) and(5Z)-6-(3-pyridyl)-5-hexen-2-amine, and (5E) and(5Z)-6-(3-pyridyl)-5-methyl-5-hexen-3-amine.

The present invention also relates to pro-drug forms of nicotiniccompounds. For example, acyl pro-drug forms of nicotinic compounds areprovided. The acyl pro-drug forms include the general formula:

and pharmaceutically acceptable salts thereof,

wherein X, X′, A, A′, A″, E^(I)-E^(VI) and Z′ are as described above,and Q′ is O, S or NR′, Q″ is O, S, NR′ or alkyl, and R′ is as definedabove. The acyl pro-drug forms of nicotinic compounds can include, forexample, amide, thioamide, carbamate, thiocarbamate, urea, and thioureaforms of the aryl substituted olefinic amine compounds described herein.Upon administration of the compound to a subject, acyl pro-drug forms asprovided herein generally are decomposed upon hydrolysis and/ormetabolization to form a pharmaceutically active aryl substitutedolefinic amine compound. These pro-drug forms, such as for example thephenyl carbamates (—NRCO₂Ph) are rapidly cleaved by plasma enzymes (H.Bungaard, In “Bioreversible Carriers in Drug Design” E. B. Roche, p. 13Pergamon, N.Y. 1987).

Representative acyl pro-drug forms of the compounds include H, alkyl,aryl, arylalkyl, and alkylaryl urea forms of(4E)-N-methyl-5-(3-pyridyl)-4-penten-2-amine,(4E)-N-methyl-5-(5-pyrimidinyl)-4-penten-2-amine,(4E)-N-methyl-5-(5-methoxy-3-pyridyl)-4-penten-2-amine,(4E)-N-methyl-5-(6-amino-5-methyl-3-pyridyl)-4-penten-2-amine,(2R)-(4E)-N-methyl-5-(3-pyridyl)-4-penten-2-amine,(2R)-(4E)-N-methyl-5-(5-isopropoxy-3-pyridyl)-4-penten-2-amine,(4E)-N-methyl-5-(5-bromo-3-pyridyl)-4-penten-2-amine,(4E)-N-methyl-5-(5-ethoxy-3-pyridyl)-4-penten-2-amine,(2S)-(4E)-N-methyl-5-(3-pyridyl)-4-penten-2-amine,(4E)-N-methyl-5-(5-isopropoxy-3-pyridyl)-4-penten-2-amine, and(2S)-(4E)-N-methyl-5-(5-isopropoxy-3-pyridyl)-4-penten-2-amine.

Other representative acyl pro-drug compounds include H, alkyl, aryl,arylalkyl, and alkylaryl thiourea forms of(4E)-N-methyl-5-(3-pyridyl)-4-penten-2-amine,(4E)-N-methyl-5-(5-pyrimidinyl)-4-penten-2-amine,(4E)-N-methyl-5-(5-methoxy-3-pyridyl)-4-penten-2-amine,(4E)-N-methyl-5-(6-amino-5-methyl-3-pyridyl)-4-penten-2-amine,(2R)-(4E)-N-methyl-5-(3-pyridyl)-4-penten-2-amine,(2R)-(4E)-N-methyl-5-(5-isopropoxy-3-pyridyl)-4-penten-2-amine,(4E)-N-methyl-5-(5-bromo-3-pyridyl)-4-penten-2-amine,(4E)-N-methyl-5-(5-ethoxy-3-pyridyl)-4-penten-2-amine,(2S)-(4E)-N-methyl-5-(3-pyridyl)-4-penten-2-amine,(4E)-N-methyl-5-(5-isopropoxy-3-pyridyl)-4-penten-2-amine, and(2S)-(4E)-N-methyl-5-(5-isopropoxy-3-pyridyl)-4-penten-2-amine.

Further representative acyl pro-drug compounds include H, alkyl, aryl,arylalkyl, and alkylaryl amide forms of(4E)-N-methyl-5-(3-pyridyl)-4-penten-2-amine,(4E)-N-methyl-5-(5-pyrimidinyl)-4-penten-2-amine,(4E)-N-methyl-5-(5-methoxy-3-pyridyl)-4-penten-2-amine,(4E)-N-methyl-5-(6-amino-5-methyl-3-pyridyl)-4-penten-2-amine,(2R)-(4E)-N-methyl-5-(3-pyridyl)-4-penten-2-amine,(2R)-(4E)-N-methyl-5-(5-isopropoxy-3-pyridyl)-4-penten-2-amine,(4E)-N-methyl-5-(5-bromo-3-pyridyl)-4-penten-2-amine,(4E)-N-methyl-5-(5-ethoxy-3-pyridyl)-4-penten-2-amine,(2S)-(4E)-N-methyl-5-(3-pyridyl)-4-penten-2-amine,(4E)-N-methyl-5-(5-isopropoxy-3-pyridyl)-4-penten-2-amine, and(2S)-(4E)-N-methyl-5-(5-isopropoxy-3-pyridyl)-4-penten-2-amine.

Additional representative acyl pro-drug compounds include H, alkyl,aryl, arylalkyl, and alkylaryl thioamide forms of(4E)-N-methyl-5-(3-pyridyl)-4-penten-2-amine,(4E)-N-methyl-5-(5-pyrimidinyl)-4-penten-2-amine,(4E)-N-methyl-5-(5-methoxy-3-pyridyl)-4-penten-2-amine,(4E)-N-methyl-5-(6-amino-5-methyl-3-pyridyl)-4-penten-2-amine,(2R)-(4E)-N-methyl-5-(3-pyridyl)-4-penten-2-amine,(2R)-(4E)-N-methyl-5-(5-isopropoxy-3-pyridyl)-4-penten-2-amine,(4E)-N-methyl-5-(5-bromo-3-pyridyl)-4-penten-2-amine,(4E)-N-methyl-5-(5-ethoxy-3-pyridyl)-4-penten-2-amine,(2S)-(4E)-N-methyl-5-(3-pyridyl)-4-penten-2-amine,(4E)-N-methyl-5-(5-isopropoxy-3-pyridyl)-4-penten-2-amine, and(2S)-(4E)-N-methyl-5-(5-isopropoxy-3-pyridyl)-4-penten-2-amine.

Yet other representative acyl pro-drug compounds include H, alkyl, aryl,arylalkyl, and alkylaryl carbamate forms of(4E)-N-methyl-5-(3-pyridyl)-4-penten-2-amine,(4E)-N-methyl-5-(5-pyrimidinyl)-4-penten-2-amine,(4E)-N-methyl-5-(5-methoxy-3-pyridyl)-4-penten-2-amine,(4E)-N-methyl-5-(6-amino-5-methyl-3-pyridyl)-4-penten-2-amine,(2R)-(4E)-N-methyl-5-(3-pyridyl)-4-penten-2-amine,(2R)-(4E)-N-methyl-5-(5-isopropoxy-3-pyridyl)-4-penten-2-amine,(4E)-N-methyl-5-(5-bromo-3-pyridyl)-4-penten-2-amine,(4E)-N-methyl-5-(5-ethoxy-3-pyridyl)-4-penten-2-amine,(2S)-(4E)-N-methyl-5-(3-pyridyl)-4-penten-2-amine,(4E)-N-methyl-5-(5-isopropoxy-3-pyridyl)-4-penten-2-amine, and(2S)-(4E)-N-methyl-5-(5-isopropoxy-3-pyridyl)-4-penten-2-amine.

Still further representative aryl pro-drug compounds include H, alkyl,aryl, arylalkyl, and alkylaryl thiocarbamate forms of(4E)-N-methyl-5-(3-pyridyl)-4-penten-2-amine,(4E)-N-methyl-5-(5-pyrimidinyl)-4-penten-2-amine,(4E)-N-methyl-5-(5-methoxy-3-pyridyl)-4-penten-2-amine,(4E)-N-methyl-5-(6-amino-5-methyl-3-pyridyl)-4-penten-2-amine,(2R)-(4E)-N-methyl-5-(3-pyridyl)-4-penten-2-amine,(2R)-(4E)-N-methyl-5-(5-isopropoxy-3-pyridyl)-4-penten-2-amine,(4E)-N-methyl-5-(5-bromo-3-pyridyl)-4-penten-2-amine,(4E)-N-methyl-5-(5-ethoxy-3-pyridyl)-4-penten-2-amine,(2S)-(4E)-N-methyl-5-(3-pyridyl)-4-penten-2-amine,(4E)-N-methyl-5-(5-isopropoxy-3-pyridyl)-4-penten-2-amine, and(2S)-(4E)-N-methyl-5-(5-isopropoxy-3-pyridyl)-4-penten-2-amine.

Acyl pro-drug forms can be synthesized by acylation of metanicotinecompounds with appropriate acylating agents. For example, amides can beprepared by reacting the amine in the metanicotine compound directlywith a carboxylic acid, using a coupling agent, such as dicyclohexylcarbodiimide (DCC), or by reacting the amine with an activatedderivative of the carboxylic acid, such as an acid halide or an acidanhydride. Thioamides can be prepared from amides using Lawesson'sreagent. Ureas can be prepared by reacting the amines in themetanicotinic compounds with isocyanates. Thioureas can be prepared in asimilar fashion using isothiocyanates. Carbamates can be formed byreacting the amines with haloformates or other carbonate-likealkoxycarbonyl transfer agents (e.g., di-t-butyl dicarbonate). Theforegoing chemistry is well known to those in the field of organicsynthesis.

Ionizable pro-drug compounds can be prepared, which provide watersolubility to pharmaceutically active compounds that would otherwise beonly slightly soluble or insoluble.

In general, the above-identified pro-drug compounds can be synthesizedby carrying out a Heck reaction (as described below) of a substitutedbromopyridine or bromopyrimidine with a pre-formed side chain containingthe pro-drug functional group, to the extent that the side chain is notincompatible with the Heck coupling chemistry.

The present invention also relates to N-oxide forms of aryl substitutedolefinic amines. The general formula for such compounds includes:

and pharmaceutically acceptable salts thereof,

wherein X is nitrogen or carbon bonded to a substituent exhibiting asigma m value in the range of about −0.3 to about 0.75. For example, Xcan be selected from N, NO, C—H, C—F, C—Cl, C—BR, C—I, C—R, C—NR′R″,C—CF₃, C—OH, C—CN, C—NO₂, C—C₂R′, C—SH, C—SCH₃, C—N₃, C—SO₂CH₃, C—OR′,C—SR′, C—C(═O)NR′R″, C—NR′C(═O)R′, C—C(═O)R′, C—C(═O)OR′, C(CH₂)_(q)OR′,C—OC(═O)R′, COC(═O)NR′R″ and C—NR′C(═O)OR′, wherein each R′ and R″ areas defined above, and wherein q is an integer from 1 to 6.

The N-oxides of the metanicotines can be synthesized using knownchemistry, for example, by protecting the N-Me functionality viabocylation with di-t-butyl dicarbonate, oxidizing the pyridine ringnitrogen with meta-chloroperoxybenzoic acid, and subsequent deprotection(debocylation) with trifluroacetic acid.

The present invention also includes metabolite forms of aryl substitutedolefinic amines. As indicated previously, the pharmaceutically activeforms of the compounds of the present invention can undergotransformation via biological processes to form metabolites. Themetabolites of the present invention include, for example, N-dealkylatedamine and monohydroxy and dihydroxy forms of the aryl substitutedolefinic amines described herein, wherein the hydroxy groups are presenton the pyridine or pyrimidine rings in the compounds.

Representative monohydroxy metabolite compounds include(4E)-N-methyl-5-(4-hydroxy-3-pyridyl)-4-penten-2-amine,(4E)-N-methyl-5-(4-hydroxy-5-pyrimidinyl)-4-penten-2-amine,(4E)-N-methyl-5-(4-hydroxy-5-methoxy-3-pyridyl)-4-penten-2-amine,(4E)-N-methyl-5-(6-amino-5-methyl-4-hydroxy-3-pyridyl)-4-penten-2-amine,(2R)-(4E) -N-methyl-5-(4-hydroxy-3-pyridyl)-4-penten-2-amine,(2R)-(4E)-N-methyl-5-(4-hydroxy-5-isopropoxy-3-pyridyl)-4-penten-2-amine,(4E)-N-methyl-5-(5-bromo-4-hydroxy-3-pyridyl)-4-penten-2-amine,(4E)-N-methyl-5-(4-hydroxy-5-ethoxy-3-pyridyl)-4-penten-2-amine,(2S)-(4E)-N-methyl-5-(4-hydroxy-3-pyridyl)-4-penten-2-amine,(4E)-N-methyl-5-(4-hydroxy-5-isopropoxy-3-pyridyl)-4-penten-2-amine, and(2S)-(4E)-N-methyl-5-(4-hydroxy-5-isopropoxy-3-pyridyl)-4-penten-2-amine.While the compounds listed above include a hydroxy group at the4-position of the pyridine ring, it is also contemplated that a hydroxygroup can be present, alternatively or in addition, at the 2 and/or 6position.

If it is desired to prepare and, optionally, administer compounds whichwould ultimately be formed as metabolites in vivo, mono- and dihydroxypyridines and pyrimidines can be used as starting materials in thesyntheses (described below) of the aryl-substituted olefinic amines,optionally with protecting groups present on the hydroxy groups. Theoptionally added protecting groups can be removed after the desiredsynthesis is otherwise complete to provide the desired compounds.

The manner in which aryl substituted olefinic amine compounds of thepresent invention are synthetically produced can vary.(E)-metanicotine-type compounds can be prepared using the techniques setforth by Löffler et al., Chem. Ber., 42, pp. 3431-3438 (1909) andLaforge, J. Amer. Chem. Soc., 50, p. 2477 (1928) from substitutednicotine-type compounds. Certain 6-substituted metanicotine-typecompounds can be prepared from the corresponding 6-substitutednicotine-type compounds using the general methods of Acheson et al., J.Chem. Soc., Perkin Trans. 1, 2, pp. 579-585 (1980). The requisiteprecursors for such compounds, 6-substituted nicotine-type compounds,can be synthesized from 6-substituted nicotinic acid esters using thegeneral methods disclosed by Rondahl, Acta Pharm. Suec., 14, pp. 113-118(1977). Preparation of certain 5-substituted metanicotine-type compoundscan be accomplished from the corresponding 5-substituted nicotine-typecompounds using the general method taught by Acheson et al., J. Chem.Soc., Perkin Trans. 1, 2, pp. 579-585 (1980). The 5-halo-substitutednicotine-type compounds (e.g., fluoro- and bromo-substitutednicotine-type compounds) and the 5-amino nicotine-type compounds can beprepared using the general procedures disclosed by Rondahl, Act. Pharm.Suec., 14, pp. 113-118 (1977). The 5-trifluoromethyl nicotine-typecompounds can be prepared using the techniques and materials set forthin Ashimori et al., Chem. Pharm. Bull., 38(9), pp. 2446-2458 (1990) andRondahl, Acta Pharm. Suec., 14, pp.113-118 (1977).

Furthermore, certain metanicotine-type compounds can be prepared by thepalladium-catalyzed coupling of an aromatic halide and a terminal olefincontaining a protected amine substituent, removing the protective groupto obtain a primary amine, and optionally alkylating the amine toprovide a secondary or tertiary amine. In particular, certainmetanicotine-type compounds can be prepared by subjecting a3-halo-substituted, 5-substituted pyridine compound or a5-halo-substituted pyrimidine compound to a palladium catalyzed couplingreaction using an olefin possessing a protected amine functionality(e.g., such an olefin provided by the reaction of a phthalimide saltwith 3-halo-1-propene, 4-halo-1-butene, 5-halo-1-pentene or6-halo-1-hexene). See, Frank et al., J. Org. Chem., 43(15), pp.2947-2949 (1978) and Malek et al., J. Org. Chem., 47, pp. 5395-5397(1982). Alternatively, certain metanicotine-type compounds can beprepared by coupling an N-protected, modified amino acid residue, suchas 4-(N-methyl-N-tert-butyloxycarbonyl)aminobutyric acid methyl ester,with an aryl lithium compound, as can be derived from a suitable arylhalide and butyl lithium. The resulting N-protected aryl ketone is thenchemically reduced to the corresponding alcohol, converted to the alkylhalide, and subsequently dehydrohalogenated to introduce the olefinfunctionality. Removal of the N-protecting group then affords thedesired metanicotine-type compound. Palladium catalyzed couplings ofterminal olefins, described above, typically yield mixtures of theolefinic isomers (e.g., E and Z and geminally substituted), wherein the(E) isomer predominates and from which it can be separated bychromatography or crystallization.

There are a number of different methods for providing(Z)-metanicotine-type compounds. In one method, (Z)-metanicotine-typecompounds can be synthesized from nicotine-type compounds as a mixtureof E and Z isomers; and the (Z)-metanicotine-type compounds can then beseparated by chromatography using the types of techniques disclosed bySprouse et al., Abstracts of Papers, p. 32, Coresta/TCRC JointConference (1972). In another method, metanicotine-type compounds can beprepared by the controlled hydrogenation of the corresponding acetyleniccompound (e.g., an N-methyl-4-(3-pyridinyl)-3-butyn-1-amine typecompound). For example, certain 5-substituted (Z)-metanicotine-typecompounds and certain 6-substituted (Z)-metanicotine-type compounds canbe prepared from 5-substituted-3-pyridinecarboxaldehydes and6-substituted-3-pyridinecarboxaldehydes, respectively. Representativesynthetic techniques for (Z)-metanicotine-type compounds are set forthin U.S. Pat. No. 5,597,919 to Dull et al.

There are a number of methods by which the (Z)-olefinic isomers of arylsubstituted olefinic amine compounds can be synthetically produced. Inone approach, the (Z)-isomers of aryl substituted olefinic aminecompounds can be prepared by the controlled hydrogenation of thecorresponding alkynyl compounds (e.g., aN-methyl-5-(3-pyridyl)-4-butyn-2-amine-type compound) using commerciallyavailable Lindlar catalyst (Aldrich Chemical Company) using themethodology set forth in H. Lindlar et al., Org. Syn. 46: 89 (1966). Therequisite alkynyl compounds can be prepared by the palladium catalyzedcoupling of an aromatic halide, preferably a 3-bromopyridine-type or a3-iodopyridine-type compound with an alkynyl side chain compound (e.g.,an N-methyl-4-pentyn-2-amine-type compound). Typically the methodologyset forth in L. Bleicher et al., Synlett. 1115 (1995) is used for thepalladium catalyzed coupling of an aryl halide with a monosubstitutedalkyne in the presence of copper(I) iodide and triphenylphosphine andpotassium carbonate as a base. Alkynyl compounds such asN-methyl-4-pentyn-2-amine can be prepared from commercially available4-pentyn-2-ol (Aldrich Chemical Company) by treatment withp-toluenesulfonyl chloride in pyridine, followed by reaction of theresulting 4-pentyn-2-ol p-toluenesulfonate with excess methylamineeither as a 40% aqueous solution or as a 2.0 M solution intetrahydrofuran. In some instances it can be necessary to protect theamino functionality of the N-methyl-4-pentyn-2-amine-type compound bytreatment with di-tert-butyl dicarbonate to give the tert-butoxycarbonylprotected amine-type compound. Such protected amine compounds canundergo the palladium catalyzed coupling with aryl halides and thesubsequent controlled hydrogenation of the resulting alkynyl compoundmore easily than the unprotected amine compounds. Thetert-butoxycarbonyl protecting group can be easily removed using astrong acid such as trifluoroacetic acid to yield the (Z)-olefinicisomers of aryl substituted olefinic amine compounds.

The methods by which aryl substituted olefinic amine compounds of thepresent invention can be synthetically produced can vary. An olefinicalcohol, such as 4-penten-2-ol, can be condensed with an aromatichalide, such as 3-bromopyridine or 3-iodopyridine. Typically, the typesof procedures set forth in Frank et al., J. Org. Chem., 43, pp.2947-2949 (1978) and Malek et al., J. Org. Chem., 47, pp. 5395-5397(1982) involving a palladium-catalyzed coupling of an olefin and anaromatic halide are used. The olefinic alcohol optionally can beprotected as a t-butyldimethylsilyl ether prior to the coupling.Desilylation then produces the olefinic alcohol. The alcoholcondensation product then is converted to an amine using the type ofprocedures set forth in deCosta et al., J. Org. Chem., 35, pp. 4334-4343(1992). Typically, the alcohol condensation product is converted to thearyl substituted olefinic amine by activation of the alcohol usingmethanesulfonyl chloride or p-toluenesulfonyl chloride, followed bymesylate or tosylate displacement using ammonia, or a primary orsecondary amine. Thus, when the amine is ammonia, an aryl substitutedolefinic primary amine compound is provided; when the amine is a primaryamine such as methylamine or cyclobutylamine, an aryl substitutedolefinic secondary amine compound is provided; and when the amine is asecondary amine such as dimethylamine or pyrrolidine, an arylsubstituted olefinic tertiary amine compound is provided. Otherrepresentative olefinic alcohols include 4-penten-1-ol, 5-hexen-2-ol,5-hexen-3-ol, 3-methyl-3-buten-1-ol, 2-methyl-3-buten-1-ol,4-methyl-4-penten-1-ol, 4-methyl-4-penten-2-ol, 1-octen-4-ol,5-methyl-1-hepten-4-ol, 4-methyl-5-hexen-2-ol, 5-methyl-5-hexen-2-ol,5-hexen-2-ol and 5-methyl-5-hexen-3-ol. Trifluoromethyl-substitutedolefinic alcohols, such as 1,1,1-trifluoro-4-penten-2-ol, can beprepared from 1-ethoxy-2,2,2-trifluoro-ethanol and allyltrimethylsilaneusing the procedures of Kubota et al., Tetrahedron Letters, 33(10), pp.1351-1354 (1992), or from trifluoroacetic acid ethyl esters andallyltributylstannane using the procedures of Ishihara et al.,Tetrahedron Letters, 34(56), pp. 5777-5780 (1993). Certain olefinicalcohols are optically active, and can be used as enantiomeric mixturesor as pure enantiomers in order to provide the corresponding opticallyactive forms of aryl substituted olefinic amine compounds. When anolefinic allylic alcohol, such as methallyl alcohol, is reacted with anaromatic halide, an aryl substituted olefinic aldehyde is produced; andthe resulting aldehyde can be converted to an aryl substituted olefinicamine compound by reductive amination (e.g., by treatment using an alkylamine and sodium cyanoborohydride). Preferred aromatic halides are3-bromopyridine-type compounds and 3-iodopyridine-type compounds.Typically, substituent groups of such 3-halopyridine-type compounds aresuch that those groups can survive contact with those chemicals (e.g.,tosylchloride and methylamine) and the reaction conditions experiencedduring the preparation of the aryl substituted olefinic amine compound.Alternatively, substituents such as —OH, —NH₂ and —SH can be protectedas corresponding acyl or trialkylsilyl compounds, or substituents suchas —NH₂ can be protected as a phthalimide functionality.

The manner in which certain aryl substituted olefinic amine compoundspossessing a branched side chain, such as(4E)-N-methyl-5-(5-isopropoxy-3-pyridyl)-4-penten-2-amine, are providedcan vary. By using one synthetic approach, the latter compound can besynthesized in a convergent manner, in which the side chain,N-methyl-N-(tert-butoxycarbonyl)-4-penten-2-amine is coupled with the3-substituted 5-halo-substituted pyridine, 5-bromo-3-isopropoxypyridine,under Heck reaction conditions, followed by removal of thetert-butoxycarbonyl protecting group. Typically, the types of proceduresset forth in W. C. Frank et al., J. Org. Chem. 43: 2947 (1978) and N. J.Malek et al., J. Org. Chem. 47: 5395 (1982) involving apalladium-catalyzed coupling of an olefin and an aromatic halide areused. The required N-methyl-N-(tert-butoxycarbonyl)-4-penten-2-amine canbe synthesized as follows: (i) Commercially available 4-penten-2-ol(Aldrich Chemical Company, Lancaster Synthesis Inc.) can be treated withp-toluenesulfonyl chloride in pyridine to yield 4-penten-2-olp-toluenesulfonate, previously described by T. Michel, et al., LiebigsAnn. 11: 1811 (1996). (ii) The resulting tosylate can be heated with 20molar equivalents of methylamine as a 40% aqueous solution to yieldN-methyl-4-penten-2-amine. (iii) The resulting amine, such as previouslymentioned by A. Viola et al., J. Chem. Soc., Chem. Commun. (21): 1429(1984), can be allowed to react with 1.2 molar equivalents ofdi-tert-butyl dicarbonate in dry tetrahydrofuran to yield the sidechain, N-methyl-N-(tert-butoxycarbonyl)-4-penten-2-amine. Thehalo-substituted pyridine, (e.g., 5-isopropoxy-3-bromopyridine) can besynthesized by two different routes. In one preparation,3,5-dibromopyridine is heated at 140° C. for 14 hours with 2 molarequivalents of potassium isopropoxide in dry isopropanol in the presenceof copper powder (5%, w/w of the 3,5-dibromopyridine) in a sealed glasstube to yield 5-isopropoxy-3-bromopyridine. This approach is amenable touse of a variety of sodium and potassium alkoxides and aryloxides,providing ready access to 5-alkoxy-3-bromopyridines,5-cycloalkoxy-3-bromopyridines, 5-phenoxy-3-bromopyridine,phenyl-substituted 5-phenoxy-3-bromopyridines and 5-fusedaryloxy-3-bromopyridines. A second preparation of5-isopropoxy-3-bromopyridine from 5-bromonicotinic acid can be performedas follows: (i) 5-Bromonicotinic acid is converted to5-bromonicotinamide by treatment with thionyl chloride, followed byreaction of the intermediate acid chloride with aqueous ammonia. (ii)The resulting 5-bromonicotinamide, previously described by C. V. Grecoet al., J. Heterocyclic Chem. 7(4): 761 (1970), is subjected to Hoffmanndegradation by treatment with sodium hydroxide and a 70% solution ofcalcium hypochlorite. (iii) The resulting 3-amino-5-bromopyridine,previously described by C. V. Greco et al., J. Heteocyclic Chem. 7(4):761 (1970), can be converted to 5-isopropoxy-3-bromopyridine bydiazotization with isoamyl nitrite under acidic conditions, followed bytreatment of the intermediate diazonium salt with isopropanol. Thepalladium-catalyzed coupling of 5-isopropoxy-3-bromopyridine andN-methyl-N-(tert-butoxycarbonyl)-4-penten-2-amine is carried out inacetonitrile-triethylamine (2:1, v,v) using a catalyst consisting of 1mole % palladium(II) acetate and 4 mole % tri-o-tolylphosphine. Thereaction can be carried out by heating the components at 80° C. for 20hours to yield(4E)-N-methyl-N-(tert-butoxycarbonyl)-5-(5-isopropoxy-3-pyridyl)-4-penten-2-amine.Removal of the tert-butoxycarbonyl protecting group can be accomplishedby treatment with 30 molar equivalents of trifluoroacetic acid inanisole at 0° C. to afford(4E)-N-methyl-5-(5-isopropoxy-3-pyridyl)-4-penten-2-amine.

The manner in which certain aryl substituted olefinic amine compoundspossessing a branched side chain are provided can vary. Using onesynthetic approach, a compound such as(4E)-N-methyl-5-(5-methoxy-3-pyridyl)-4-penten-2-amine can besynthesized by coupling a halo-substituted pyridine,5-bromo-3-methoxypyridine with an olefin containing a secondary alcoholfunctionality, 4-penten-2-ol, under Heck reaction conditions; and theresulting pyridyl alcohol intermediate can be converted to itsp-toluenesulfonate ester, followed by treatment with methylamine.Typically, the types of procedures set forth in W. C. Frank et al., J.Org. Chem. 43: 2947 (1978) and N. J. Malek et al., J. Org. Chem. 47:5395 (1982) involving a palladium-catalyzed coupling of an olefin and anaromatic halide are used. The required halo-substituted pyridine,5-bromo-3-methoxypyridine is synthesized using methodology similar tothat described by H. J. den Hertog et al., Recl. Trav. Chim. Pays-Bas74:1171 (1955), namely by heating 3,5-dibromopyridine with 2.5 molarequivalents of sodium methoxide in dry methanol in the presence ofcopper powder (5%, w/w of the 3,5-dibromopyridine) in a sealed glasstube at 150° C. for 14 hours to produce 5-bromo-3-methoxypyridine. Theresulting 5-bromo-3-methoxypyridine, previously described by D. L.Comins, et al., J. Org. Chem. 55: 69 (1990), can be coupled with4-penten-2-ol in acetonitrile-triethylamine (1.1:1, v/v) using acatalyst consisting of 1 mole % palladium(II) acetate and 4 mole %tri-o-tolylphosphine. The reaction is carried out by heating thecomponents in a sealed glass tube at 140° C. for 14 hours to yield(4E)-N-methyl-5-(5-methoxy-3-pyridyl)-4-penten-2-ol. The resultingalcohol is treated with 2 molar equivalents of p-toluenesulfonylchloride in dry pyridine at 0° C. to produce(4E)-N-methyl-5-(5-methoxy-3-pyridyl)-4-penten-2-ol p-toluenesulfonate.The tosylate intermediate is treated with 120-molar equivalents ofmethylamine as a 40% aqueous solution, containing a small amount ofethanol as a co-solvent to produce(4E)-N-methyl-5-(5-methoxy-3-pyridyl)-4-penten-2-amine.

The manner in which optically active forms of certain aryl substitutedolefinic amine compounds, such as(2S)-(4E)-N-methyl-5-(3-pyridyl)-4-penten-2-amine, are provided canvary. In one synthetic approach, the latter type of compound issynthesized by coupling a halo-substituted pyridine, 3-bromopyridine,with an olefin possessing a single enantiomer secondary alcoholfunctionality, (2R)-4-penten-2-ol, under Heck reaction conditions. Theresulting enantiomerically pure pyridyl alcohol intermediate,(2R)-(4E)-5-(3-pyridyl)-4-penten-2-ol is converted to its correspondingp-toluenesulfonate ester, which is subsequently treated withmethylamine, resulting in tosylate displacement with inversion ofconfiguration. Typically, the types of procedures set forth in W. C.Frank et al., J. Org. Chem. 43: 2947 (1978) and N. J. Malek et al., J.Org. Chem. 47: 5395 (1982) involving a palladium-catalyzed coupling ofan aromatic halide and an olefin are used. The enantiomerically pureside chain, (2R)-4-penten-2-ol can be prepared by treatment of theepoxide, (R)-(+)-propylene oxide (commercially available from FlukaChemical Company) with vinylmagnesium bromide in tetrahydrofuran at lowtemperatures (−25 to −10° C.) using the general synthetic methodology ofA. Kalivretenos, J. K. Stille, and L. S. Hegedus, J. Org. Chem. 56: 2883(1991). The Heck reaction of (2R)-4-penten-2-ol with 3-bromopyridine iscarried out in acetonitrile-triethylamine (1:1, v/v) using a catalystconsisting of 1 mole % palladium(II) acetate and 4 mole %tri-o-tolylphosphine. The reaction is done by heating the components at140° C. for 14 hours in a sealed glass tube. The product,(2R)-(4E)-5-(3-pyridyl)-4-penten-2-ol, is treated with 3 molarequivalents of p-toluenesulfonyl chloride in dry pyridine at 0° C., toafford the tosylate intermediate. The p-toluenesulfonate ester is heatedwith 82 molar equivalents of methylamine as a 40% aqueous solution,containing a small amount of ethanol as a co-solvent, to produce(2S)-(4E)-N-methyl-5-(3-pyridyl)-4-penten-2-amine. In a similar manner,the corresponding aryl substituted olefinic amine enantiomer, such as(2R)-(4E)-N-methyl-5-(3-pyridyl)-4-penten-2-amine, can be synthesized bythe Heck coupling of 3-bromopyridine and (2S)-4-penten-2-ol. Theresulting intermediate, (2S)-(4E)-5-(3-pyridyl)-4-penten-2-ol, isconverted to its p-toluenesulfonate, which is subjected to methylaminedisplacement. The single enantiomer alcohol, (2S)-4-penten-2-ol, isprepared from (S)-(−)-propylene oxide (commercially available fromAldrich Chemical Company) using a procedure analogous to that describedfor the preparation of (2R)-4-penten-2-ol from (R)-(+)-propylene oxideas reported by A. Kalivretenos, J. K. Stille, and L. S. Hegedus, J. Org.Chem. 56: 2883 (1991).

The manner in which single enantiomer compounds of the present inventioncan be made can vary. The aforementioned olefinic side chain,N-methyl-N-(tert-butoxycarbonyl)-4-penten-2-amine, can be produced aseither the (R) or the (S) enantiomer by chemistry similar to thatdescribed above. Thus treatment of either (R)-4-penten-2-ol or(S)-4-penten-2-ol (the syntheses of which were previously described)with p-toluenesulfonyl chloride produces the corresponding 4-penten-2-olp-toluenesulfonate. The tosylate intermediate is treated with 40%aqueous methylamine and DMF (as co-solvent) to produce either (R)- or(S)-N-methyl-4-penten-2-amine, by inversion of configuration. Reactionwith di-t-butyl dicarbonate then generates the corresponding (R)- and(S)-N-methyl-N-(tert-butoxycarbonyl)-4-penten-2-amine, the palladiumcatalyzed coupling of which leads to single enantiomer forms ofcompounds of the present invention.

The manner in which various hydroxylated compounds of the presentinvention (the aforementioned mono- and dihydroxy metabolites of themetanicotines) can be made can vary. The following schemes areillustrative.

Scheme I shows the synthesis of(S)-N-methyl-5-(2,4-dihydroxy-5-pyrimidinyl)-4-penten-2-amine. In thissynthesis, the previously described(S)-N-methyl-N-(tert-butoxycarbonyl)-4-penten-2-amine is subjected toHeck-type coupling conditions by reaction with a2,4-dimethoxy-3-iodopyrimidine in the presence of a palladium catalystto form(S)-N-methyl-N-(tert-butoxycarbonyl)-5-(2,4-dimethoxy-5-pyrimidinyl)-4-penten-2-amine.The methoxy groups can be converted to hydroxy groups, concurrent withthe cleavage of the amine protecting group, by reaction withtrimethylsilyl iodide in methanol/dichloromethane to yield the desiredN-methyl-5-(2,4-dihydroxy-5-pyrimidinyl)-4-penten-2-amine compound as ahydroiodide salt. Alternately, the tert-butoxycarbonyl protecting groupcan be selectively removed by trifluoroacetic acid, as describedpreviously, to give the(S)-N-methyl-5-(2,4-dimethoxy-5-pyrimidinyl)-4-penten-2-amine. Cleavageof the methyl ethers using 48% HBr then provides(S)-N-methyl-5-(2,4-dihydroxy-5-pyrimidinyl)-4-penten-2-amine.

Scheme II shows a similar synthesis for(S)-N-methyl-5-(2-hydroxy-5-pyrimidinyl)-4-penten-2-amine (a monohydroxymetabolite). It illustrates the use of silyl protecting groups for thehydroxy substituents. Thus, 5-bromo-2-(trimethylsilyloxy)pyrimidine canbe used in a Heck-type coupling reaction with the aforementioned(S)-N-methyl-N-(tert-butoxycarbonyl)-4-penten-2-amine. The simultaneousremoval of both the silyl and tert-butoxycarbonyl protecting groups canbe effected by treatment with trifluoroacetic acid. This sequence ofreactions is equally applicable to other monohydroxy halopyrimidines.

The present invention also relates to methods for preventing a conditionor disorder in a subject susceptible to such a condition or disorder,and/or for providing treatment to a subject suffering therefrom, whereinthe disorder itself or exhibited symptoms are effected by the method.For example, the method comprises administering to a patient an amountof a compound effective for providing some degree of prevention of theprogression of a CNS disorder (i.e., provide protective effects),amelioration of the symptoms of a CNS disorder, and amelioration of therecurrence of a CNS disorder. The method involves administering aneffective amount of a compound selected from the general formulae whichare set forth hereinbefore. The present invention relates to apharmaceutical composition incorporating a compound selected from thegeneral formulae which are set forth hereinbefore. Chiral compounds canbe employed as racemic mixtures or as single enantiomers. The compoundscan be employed in a free base form or in a salt form (e.g., aspharmaceutically acceptable salts). Examples of suitablepharmaceutically acceptable salts include inorganic acid addition saltssuch as hydrochloride, hydrobromide, sulfate, phosphate, and nitrate;organic acid addition salts such as acetate, galactarate, propionate,succinate, lactate, glycolate, malate, tartrate, citrate, maleate,fumarate, methanesulfonate, p-toluenesulfonate, and ascorbate; saltswith acidic amino acid such as aspartate and glutamate; alkali metalsalts such as sodium salt and potassium salt; alkaline earth metal saltssuch as magnesium salt and calcium salt; ammonium salt; organic basicsalts such as trimethylamine salt, triethylamine salt, pyridine salt,picoline salt, dicyclohexylamine salt, and N,N′-dibenzylethylenediaminesalt; and salts with basic amino acid such as lysine salt and argininesalt. The salts can be in some cases hydrates or ethanol solvates.Representative salts are provided as described in U.S. Pat. No.5,597,919 to Dull et al., U.S. Pat. No. 5,616,716 to Dull et al. andU.S. Pat. No. 5,663,356 to Ruecroft et al.

The compounds described herein are useful for treating those types ofconditions and disorders for which other types of nicotinic compoundshave been proposed as therapeutics. See, for example, Williams et al.DN&P 7(4):205-227 (1994), Arneric et al., CNS Drug Rev. 1(1): 1-26(1995), Arneric et al., Exp. Opin. Invest. Drugs 5(1):79-79-100 (1996),Bencherif et al., JPET 279:1413 (1996), Lippiello et al., JPET 279:1422(1996), Damaj et al., Neuroscience (1997), Holladay et al., J. Med. Chem40(28): 4169-4194 (1997), Bannon et al., Science 279: 77-80 (1998), PCTWO 94/08992, PCT WO 96/31475, and U.S. Pat. Nos. 5,583,140 to Bencherifet al., 5,597,919 to Dull et al., and 5,604,231 to Smith et al.Compounds of the present invention can be used as analgesics, to treatulcerative colitis, and to treat convulsions such as those that aresymptomatic of epilepsy. CNS disorders which can be treated inaccordance with the present invention include presenile dementia (earlyonset Alzheimer's disease), senile dementia (dementia of the Alzheimer'stype), Parkinsonism including Parkinson's disease, Huntington's chorea,tardive dyskinesia, hyperkinesia, mania, attention deficit disorder,anxiety, dyslexia, schizophrenia and Tourette's syndrome.

The pharmaceutical composition also can include various other componentsas additives or adjuncts. Exemplary pharmaceutically acceptablecomponents or adjuncts which are employed in relevant circumstancesinclude antioxidants, free radical scavenging agents, peptides, growthfactors, antibiotics, bacteriostatic agents, immunosuppressives,anticoagulants, buffering agents, anti-inflammatory agents,anti-pyretics, time release binders, anesthetics, steroids andcorticosteroids. Such components can provide additional therapeuticbenefit, act to affect the therapeutic action of the pharmaceuticalcomposition, or act towards preventing any potential side effects whichcan be posed as a result of administration of the pharmaceuticalcomposition. In certain circumstances, a compound of the presentinvention can be employed as part of a pharmaceutical composition withother compounds intended to prevent or treat a particular disorder.

The manner in which the compounds are administered can vary. Thecompounds can be administered by inhalation (e.g., in the form of anaerosol either nasally or using delivery articles of the type set forthin U.S. Pat. No. 4,922,901 to Brooks et al.); topically (e.g., in lotionform); orally (e.g., in liquid form within a solvent such as an aqueousor non-aqueous liquid, or within a solid carrier); intravenously (e.g.,within a dextrose or saline solution); as an infusion or injection(e.g., as a suspension or as an emulsion in a pharmaceuticallyacceptable liquid or mixture of liquids); intrathecally;intracerebroventricularly; or transdermally (e.g., using a transdermalpatch). Although it is possible to administer the compounds in the formof a bulk active chemical, it is preferred to present each compound inthe form of a pharmaceutical composition or formulation for efficientand effective administration. Exemplary methods for administering suchcompounds will be apparent to the skilled artisan. For example, thecompounds can be administered in the form of a tablet, a hard gelatincapsule or as a time release capsule. As another example, the compoundscan be delivered transdermally using the types of patch technologiesavailable from Novartis and Alza Corporation. The administration of thepharmaceutical compositions of the present invention can beintermittent, or at a gradual, continuous, constant or controlled rateto a warm-blooded animal, (e.g., a mammal such as a mouse, rat, cat,rabbit, dog, pig, cow, or monkey); but advantageously is preferablyadministered to a human being. In addition, the time of day and thenumber of times per day that the pharmaceutical formulation isadministered can vary. Administration preferably is such that the activeingredients of the pharmaceutical formulation interact with receptorsites within the body of the subject that affect the functioning of theCNS. More specifically, in treating a CNS disorder administrationpreferably is such so as to optimize the effect upon those relevantreceptor subtypes which have an effect upon the functioning of the CNS,while minimizing the effects upon muscle-type receptor subtypes. Othersuitable methods for administering the compounds of the presentinvention are described in U.S. Pat. No. 5,604,231 to Smith et al., thedisclosure of which is incorporated herein by reference in its entirety.

The appropriate dose of the compound is that amount effective to preventoccurrence of the symptoms of the disorder or to treat some symptoms ofthe disorder from which the patient suffers. By “effective amount”,“therapeutic amount” or “effective dose” is meant that amount sufficientto elicit the desired pharmacological or therapeutic effects, thusresulting in effective prevention or treatment of the disorder. Thus,when treating a CNS disorder, an effective amount of compound is anamount sufficient to pass across the blood-brain barrier of the subject,to bind to relevant receptor sites in the brain of the subject, and toactivate relevant nicotinic receptor subtypes (e.g., provideneurotransmitter secretion, thus resulting in effective prevention ortreatment of the disorder). Prevention of the disorder is manifested bydelaying the onset of the symptoms of the disorder. Treatment of thedisorder is manifested by a decrease in the symptoms associated with thedisorder or an amelioration of the recurrence of the symptoms of thedisorder. Relative to (E)-metanicotine, compounds of the presentinvention are less extensively metabolized (i.e., fewer metabolites areformed, and the rate of elimination from blood is slower) in mammaliansystems. This is particularly true in those embodiments where E^(V)and/or E^(VI) is C₁₋₅ alkyl, preferably methyl. As such, as compared to(E)-metanicotine, compounds of the present invention are capable ofproviding higher absolute plasma concentrations, and are capable ofbeing maintained within a mammalian system for longer periods of time.Thus, compounds of the present invention are capable of providingcomparable therapeutic effects of (E)-metanicotine at low doses.

The effective dose can vary, depending upon factors such as thecondition of the patient, the severity of the symptoms of the disorder,and the manner in which the pharmaceutical composition is administered.For human patients, the effective dose of typical compounds generallyrequires administering the compound in an amount sufficient to activaterelevant receptors to effect neurotransmitter (e.g., dopamine) releasebut the amount should be insufficient to induce effects on skeletalmuscles and ganglia to any significant degree. The effective dose ofcompounds will of course differ from patient to patient but in generalincludes amounts starting where CNS effects or other desired therapeuticeffects occur, but below the amount where muscular effects are observed.

Typically, the effective dose of compounds generally requiresadministering the compound in an amount of less than 5 mg/kg of patientweight. Often, the compounds of the present invention are administeredin an amount from 1 mg to less than 100 ug/kg of patient weight,frequently between about 10 ug to less than 100 ug/kg of patient weight,and preferably between about 10 ug to about 50 ug/kg of patient weight.For compounds of the present invention that do not induce effects onmuscle type nicotinic receptors at low concentrations, the effectivedose is less than 5 mg/kg of patient weight; and often such compoundsare administered in an amount from 50 ug to less than 5 mg/kg of patientweight. The foregoing effective doses typically represent that amountadministered as a single dose, or as one or more doses administered overa 24 hour period.

For human patients, the effective dose of typical compounds generallyrequires administering the compound in an amount of at least about 1,often at least about 10, and frequently at least about 25 ug/24hr./patient. For human patients, the effective dose of typical compoundsrequires administering the compound which generally does not exceedabout 500, often does not exceed about 400, and frequently does notexceed about 300 ug/24 hr./patient. In addition, administration of theeffective dose is such that the concentration of the compound within theplasma of the patient normally does not exceed 500 ng/ml, and frequentlydoes not exceed 100 ng/ml.

The compounds useful according to the method of the present inventionhave the ability to pass across the blood-brain barrier of the patient.As such, such compounds have the ability to enter the central nervoussystem of the patient. The log P values of typical compounds, which areuseful in carrying out the present invention are generally greater thanabout 0, often are greater than about 0.5, and frequently are greaterthan about 1. The log P values of such typical compounds generally areless than about 3.5, often are less than about 3, and sometimes are lessthan about 2.5. Log P values provide a measure of the ability of acompound to pass across a diffusion barrier, such as a biologicalmembrane. See, Hansch, et al., J. Med. Chem. 11:1 (1968).

The compounds useful according to the method of the present inventionhave the ability to bind to, and in most circumstances, cause activationof, nicotinic cholinergic receptors of the brain of the patient (e.g.,such as those receptors that modulate dopamine release). As such, suchcompounds have the ability to express nicotinic pharmacology, and inparticular, to act as nicotinic agonists. The receptor binding constantsof typical compounds useful in carrying out the present inventiongenerally exceed about 0.1 nM, often exceed about 1 nM, and frequentlyexceed about 10 nM. The receptor binding constants of such typicalcompounds generally are less than about 1 uM, often are less than about100 nM, and frequently are less than about 50 nM. Receptor bindingconstants provide a measure of the ability of the compound to bind tohalf of the relevant receptor sites of certain brain cells of thepatient. See, Cheng, et al., Biochem. Pharmacol. 22:3099 (1973).

The compounds useful according to the method of the present inventionhave the ability to demonstrate a nicotinic function by effectivelyeliciting ion flux through, and/or neurotransmitter secretion from,nerve ending preparations (e.g., thalamic or striatal synaptosomes). Assuch, such compounds have the ability to cause relevant neurons tobecome activated, and to release or secrete acetylcholine, dopamine, orother neurotransmitters. Generally, typical compounds useful in carryingout the present invention effectively provide for relevant receptoractivation in amounts of at least about 30 percent, often at least about50 percent, and frequently at least about 75 percent, of that maximallyprovided by (S)-(−)-nicotine. Generally, typical compounds useful incarrying out the present invention are more potent than (S)-(−)-nicotinein eliciting relevant receptor activation. Generally, typical compoundsuseful in carrying out the present invention effectively provide for thesecretion of dopamine in amounts of at least about 50 percent, often atleast about 75 percent, and frequently at least about 100 percent, ofthat maximally provided by (S)-(−)-nicotine. Certain compounds of thepresent invention can provide secretion of dopamine in an amount whichcan exceed that maximally provided by (S)-(−)-nicotine. Generally,typical compounds useful in carrying out the present invention are lesspotent than (S)-(−)-nicotine in eliciting neurotransmitter secretion,such as dopamine secretion.

The compounds of the present invention, when employed in effectiveamounts in accordance with the method of the present invention, lack theability to elicit activation of nicotinic receptors of human muscle toany significant degree. In that regard, the compounds of the presentinvention demonstrate poor ability to cause isotopic rubidium ion fluxthrough nicotinic receptors in cell preparations expressing muscle-typenicotinic acetylcholine receptors. Thus, such compounds exhibit receptoractivation constants or EC₅₀ values (i.e., which provide a measure ofthe concentration of compound needed to activate half of the relevantreceptor sites of the skeletal muscle of a patient) which are extremelyhigh (i.e., greater than about 100 uM). Generally, typical preferredcompounds useful in carrying the present invention activate isotopicrubidium ion flux by less than 10 percent, often by less than 5 percent,of that maximally provided by S(−) nicotine.

The compounds of the present invention, when employed in effectiveamounts in accordance with the method of the present invention, areselective to certain relevant nicotinic receptors, but do not causesignificant activation of receptors associated with undesirable sideeffects. By this is meant that a particular dose of compound resultingin prevention and/or treatment of a CNS disorder, is essentiallyineffective in eliciting activation of certain ganglionic-type nicotinicreceptors. This selectivity of the compounds of the present inventionagainst those receptors responsible for cardiovascular side effects isdemonstrated by a lack of the ability of those compounds to activatenicotinic function of adrenal chromaffin tissue. As such, such compoundshave poor ability to cause isotopic rubidium ion flux through nicotinicreceptors in cell preparations derived from the adrenal gland.Generally, typical preferred compounds useful in carrying out thepresent invention activate isotopic rubidium ion flux by less than 10percent, often by less than 5 percent, of that maximally provided byS(−) nicotine.

Compounds of the present invention, when employed in effective amountsin accordance with the method of the present invention, are effectivetowards providing some degree of prevention of the progression of CNSdisorders, amelioration of the symptoms of CNS disorders, andamelioration to some degree of the recurrence of CNS disorders. However,such effective amounts of those compounds are not sufficient to elicitany appreciable side effects, as is demonstrated by decreased effects onpreparations believed to reflect effects on the cardiovascular system,or effects to skeletal muscle. As such, administration of compounds ofthe present invention provides a therapeutic window in which treatmentof certain CNS disorders is provided, and side effects are avoided. Thatis, an effective dose of a compound of the present invention issufficient to provide the desired effects upon the CNS, but isinsufficient (i.e., is not at a high enough level) to provideundesirable side effects. Preferably, effective administration of acompound of the present invention resulting in treatment of CNSdisorders occurs upon administration of less ⅓, frequently less than ⅕,and often less than 1/10, that amount sufficient to cause any sideeffects to a significant degree.

The following examples are provided to illustrate the present invention,and should not be construed as limiting thereof. In these examples, allparts and percentages are by weight, unless otherwise noted. Reactionyields are reported in mole percentages. Several commercially availablestarting materials are used throughout the following examples.3-Bromopyridine, 3,5-dibromopyridine, 5-bromonicotinic acid,5-bromopyrimidine, and 4-penten-2-ol were obtained from Aldrich ChemicalCompany or Lancaster Synthesis Inc. 2-Amino-5-bromo-3-methylpyridine waspurchased from Canbridge Chemical Company Ltd. (R)-(+)-propylene oxidewas obtained from Fluka Chemical Company, and (S)-(−)-propylene oxidewas obtained from Aldrich Chemical Company. In the syntheses describedherein, synonyms for propylene oxide are epoxypropane; 1,2-epoxypropane;methyl ethylene oxide; methyl oxirane; propene oxide; and 1,2-propyleneoxide.

Column chromatography was done using either Merck silica gel 60 (70-230mesh) or aluminum oxide (activated, neutral, Brockmann I, standardgrade, ˜150 mesh). Pressure reactions were done in a heavy wall glasspressure tube (185 mL capacity), with Ace-Thread, and plunger valveavailable from Ace Glass Inc. Reaction mixtures were typically heatedusing a high-temperature silicon oil bath, and temperatures refer tothose of the oil bath. The following abbreviations are used in thefollowing examples: CHCl₃ for chloroform, CH₂Cl₂ for dichloromethane,CH₃OH for methanol, DMF for N,N-dimethylformamide, and EtOAc for ethylacetate, THF for tetrahydrofuran, and Et₃N for triethylamine.

EXAMPLE 1

Determination of Log P Value

Log P values, which have been used to assess the relative abilities ofcompounds to pass across the blood-brain barrier (Hansch, et al., J.Med. Chem. 11:1 (1968)), were calculated using the Cerius² softwarepackage Version 3.5 by Molecular Simulations, Inc.

EXAMPLE 2

Determination of Binding to Relevant Receptor Sites

Binding of the compounds to relevant receptor sites was determined inaccordance with the techniques described in U.S. Pat. No. 5,597,919 toDull et al. Inhibition constants (Ki values), reported in nM, werecalculated from the IC₅₀ values using the method of Cheng et al.,Biochem, Pharmacol. 22:3099 (1973).

EXAMPLE 3

Determination of Dopamine Release

Dopamine release was measured using the techniques described in U.S.Pat. No. 5,597,919 to Dull et al. Release is expressed as a percentageof release obtained with a concentration of (S)-(−)-nicotine resultingin maximal effects. Reported EC₅₀ values are expressed in nM, andE_(max) values represent the amount released relative to(S)-(−)-nicotine on a percentage basis.

EXAMPLE 4

Determination of Rubidium Ion Release

Rubidium release was measured using the techniques described inBencherif et al., JPET, 279: 1413-1421 (1996). Reported EC₅₀ values areexpressed in nM, and E_(max) values represent the amount of rubidium ionreleased relative to 300 uM tetramethylammonium ion, on a percentagebasis.

EXAMPLE 5

Determination of Interaction with Muscle Receptors

The determination of the interaction of the compounds with musclereceptors was carried out in accordance with the techniques described inU.S. Pat. No. 5,597,919 to Dull et al. The maximal activation forindividual compounds (E_(max)) was determined as a percentage of themaximal activation induced by (S)-(−)-nicotine. Reported E_(max) valuesrepresent the amount released relative to (S)-(−)-nicotine on apercentage basis.

EXAMPLE 6

Determination of Interaction with Ganglion Receptors

The determination of the interaction of the compounds with ganglionicreceptors was carried out in accordance with the techniques described inU.S. Pat. No. 5,597,919 to Dull et al. The maximal activation forindividual compounds (E_(max)) was determined as a percentage of themaximal activation induced by (S)-(−)-nicotine. Reported E_(max) valuesrepresent the amount released relative to (S)-(−)-nicotine on apercentage basis.

EXAMPLE 7

Sample No. 1 is (4E)-N-methyl-5-(3-pyridyl)-4-penten-2-aminehemigalactarate, which was prepared in accordance with the followingtechniques:

(4E)-5-(3-Pyridyl)-4-penten-2-ol.

A mixture of 3-bromopyridine (7.50 g, 47.46 mmol), 4-penten-2-ol (4.90g, 56.96 mmol), palladium(II) acetate (106 mg, 0.47 mmol),tri-o-tolylphosphine (575 mg, 1.89 mmol), triethylamine (28.4 mL, 204.11mmol) and acetonitrile (25 mL) were heated in a sealed glass tube at140° C. for 14 h. The reaction mixture was cooled to ambienttemperature, diluted with water, and extracted with chloroform (3×200mL). The combined chloroform extracts were dried over sodium sulfate,filtered, and concentrated by rotary evaporation to give a pale-yellowoil (7.50 g, 81.0%).

(4E)-5-(3-Pyridyl)-4-penten-2-ol p-Toluenesulfonate

To a stirred solution of (4E)-5-(3-pyridyl)-4-penten-2-ol (5.00 g, 30.67mmol) in dry pyridine (30 mL) at 0° C. was added p-toluenesulfonylchloride (8.77 g, 46.01 mmol). The reaction mixture was stirred for 24 hat ambient temperature. The pyridine was removed by rotary evaporation.Toluene (50 mL) was added to the residue and subsequently removed byrotary evaporation. The crude product was stirred with a saturatedsolution of sodium bicarbonate (100 mL) and extracted with chloroform(3×100 mL). The combined chloroform extracts were dried over sodiumsulfate, filtered, and concentrated by rotary evaporation. The crudeproduct was purified by column chromatography over aluminum oxide,eluting with ethyl acetate-hexane (3:7, v/v). Selected fractions werecombined and concentrated by rotary evaporation to give a viscous, brownoil (5.83 g, 60.1%).

(4E)-N-Methyl-5-(3-pyridyl)-4-penten-2-amine

A mixture of (4E)-5-(3-pyridyl)-4-penten-2-ol p-toluenesulfonate (5.60g, 17.66 mmol), methylamine (100 mL, 40% solution in water), and ethylalcohol (10 mL) was stirred at ambient temperature for 18 h. Theresulting solution was extracted with chloroform (3×100 mL). Thecombined chloroform extracts were dried over sodium sulfate, filtered,and concentrated by rotary evaporation. The crude product was purifiedby column chromatography over aluminum oxide, eluting with ethylacetate-methanol (7:3, v/v). Selected fractions were combined andconcentrated by rotary evaporation, producing an oil. Furtherpurification by vacuum distillation furnished 1.60 g (51.6%) of acolorless oil, bp 110-120° C. at 0.1 mm Hg.

(4E)-N-Methyl-5-(3-pyridyl)-4-penten-2-amine Hemigalactarate

(4E)-N-Methyl-5-(3-pyridyl)-4-penten-2-amine (1.60 g, 9.10 mmol) wasdissolved in ethyl alcohol (20 mL), assisted by warming to 60° C. Thewarm solution was treated with galactaric acid (955 mg, 4.54 mmol) inone portion, followed by the dropwise addition of water (0.5 mL). Thesolution was filtered while hot to remove some insoluble material. Thefiltrate was allowed to cool to ambient temperature. The resultingcrystals were filtered, washed with anhydrous diethyl ether, and driedunder vacuum at 40° C. to yield 1.20 g (47.0%) of a white, crystallinepowder, mp 148-150° C.

Sample No. 1 exhibits a log P of 1.924, and such a favorable log P valueindicates that the compound has the capability of passing theblood-brain barrier. The sample exhibits a Ki of 83 nM. The low bindingconstant indicates that the compound exhibits good high affinity bindingto certain CNS nicotinic receptors.

Sample No. 1 exhibits an EC₅₀ value of 6600 nM and an E_(max) value of113% for dopamine release, indicating that the compound inducesneurotransmitter release thereby exhibiting known nicotinicpharmacology. The sample exhibits an EC₅₀ value of 3100 nM and anE_(max) value of 35% in the rubidium ion flux assay, indicating that thecompound effectively induces activation of CNS nicotinic receptors.

Sample No. 1 exhibits an E_(max) of 13% (at a concentration of 100 uM)at muscle-type receptors, indicating that the compound does not induceactivation of muscle-type receptors. The sample exhibits an E_(max) of62% (at a concentration of 100 uM) at ganglionic-type receptors. Atcertain levels the compound shows CNS effects to a significant degreebut show neither undesirable muscle nor ganglion effects to anysignificant degree. The compound begins to cause muscle and ganglioneffects only when employed in amounts of several times those required toactivate rubidium ion flux and dopamine release, thus indicating a lackof certain undesirable side effects in subjects receiving administrationof that compound.

EXAMPLE 8

Sample No. 2 is (2R)-(4E)-N-methyl-5-(3-pyridyl)-4-penten-2-aminehemigalactarate, which was prepared in accordance with the followingtechniques:

(2S)-4-Penten-2-ol

(2S)-4-Penten-2-ol was prepared from (S)-(−)-propylene oxide using aprocedure similar to that described for the preparation of(2R)-4-penten-2-ol from (R)-(+)-propylene oxide as detailed in A.Kalivretenos, J. K. Stille, and L. S. Hegedus, J. Org. Chem. 56: 2883(1991). Thus, a 1.0M solution of vinylmagnesium bromide in THF (129 mL,129.0 mmol) was slowly added to a suspension of copper(I) iodide (2.46g, 12.92 mmol) in dry THF (40 mL, distilled from sodium andbenzophenone) at −25° C. After stirring 5 min, a solution of(S)-(−)-propylene oxide (5.00 g, 86.1 mmol) in dry THF (5 mL) was added.The mixture was allowed to warm to −10° C. and placed in a freezer at 0°C. for 12 h. The mixture was stirred for an additional 1 h at 0° C. andpoured into a mixture of saturated ammonium chloride solution (100 mL)and ice (100 g). The mixture was stirred for 4 h and extracted withether (3×100 mL). The combined ether extracts were dried (K₂CO₃),filtered, and concentrated under reduced pressure by rotary evaporationat 0° C. The resulting brown oil was vacuum distilled to yield 5.86 g(79.1%) of a colorless distillate, bp 37-39° C. at 9 mm Hg.

(2S)-(4E)-5-(3-Pyridyl)-4-penten-2-ol

A mixture of 3-bromopyridine (11.22 g, 70.58 mmol), (2S)-4-penten-2-ol(5.00 g, 58.05 mmol), palladium(II) acetate (527 mg, 2.35 mmol),tri-o-tolylphosphine (1.79 g, 5.88 mmol), triethylamine (30 mL, 216mmol) and acetonitrile (30 mL) were heated in a sealed glass tube at130-140° C. for 8 h. The reaction mixture was cooled to ambienttemperature. The solvent was removed under reduced pressure on a rotaryevaporator. Water (20 mL) was added and the mixture was extracted withchloroform (4×50 mL). The combined chloroform extracts were dried(K₂CO₃), filtered, and concentrated by rotary evaporation, producing apale-yellow oil (6.00 g). The crude product was purified by columnchromatography over silica gel, eluting with chloroform-acetone (95:5,v/v). Selected fractions were combined and concentrated by rotaryevaporation, affording 3.95 g (41.7%) of a pale-yellow oil.

(2S)-(4E)-5-(3-Pyridyl)-4-penten-2-ol p-Toluenesulfonate

Under a nitrogen atmosphere, p-toluenesulfonyl chloride (7.01 g, 36.77mmol) was added to a stirring solution of(2S)-(4E)-5-(3-pyridyl)-4-penten-2-ol (3.00 g, 18.38 mmol) in drytriethylamine (20 mL) at 0° C. After stirring and warming to ambienttemperature over 18 h, the mixture was stirred with cold, saturatedNaHCO₃ solution (50 mL) for 1 hour and extracted with chloroform (3×50mL). The combined chloroform extracts were dried (K₂CO₃), filtered, andconcentrated by rotary evaporation to afford a thick, dark-brown mass(˜7 g). The crude product was purified by column chromatography onsilica gel, eluting with chloroform-acetone (98:2, v/v) to afford 4.00 g(68.6%) of a light-brown syrup.

(2R)-(4E)-N-Methyl-5-(3-pyridyl)-4-penten-2-amine

A mixture of (2S)-(4E)-5-(3-pyridyl)-4-penten-2-ol p-toluenesulfonate(3.80 g, 11.97 mmol) and methylamine (20 mL, 2.0M solution in THF) washeated at 100-110° C. for 8 h in a sealed glass tube. The mixture wascooled to ambient temperature and concentrated under reduced pressure ona rotary evaporator. The resulting brown syrup was diluted withsaturated NaHCO₃ solution (25 mL) and extracted with chloroform (4×25mL). The combined chloroform extracts were dried (K₂CO₃), filtered, andconcentrated by rotary evaporation to afford a thick, brown syrup (2.00g). The crude product was purified by column chromatography on silicagel, eluting with chloroform-methanol (95:5, v/v). Selected fractionswere combined, concentrated by rotary evaporation affording a 800 mg(37.9%) of a pale-yellow oil.

(2R)-(4E)-N-Methyl-5-(3-pyridyl)-4-penten-2-amine Hemigalactarate

Galactaric acid (328.0 mg, 1.56 mmol) and(2R)-(4E)-N-methyl-5-(3-pyridyl)-4-penten-2-amine (600.0 mg, 3.40 mmol)were dissolved in 2-propanol (5 mL) and water (0.2 mL), assisted byheating and sonication. The hot solution was filtered to remove someinsoluble material. The solvent was removed on a rotary evaporator, andthe residue was dried under high vacuum, producing a cream-coloredsyrup. The syrup was dissolved in dry 2-propanol (5 mL) and cooled at 4°C. The resulting precipitate was filtered and dried under high vacuum toyield 700 mg (79.7%) of an off-white, crystalline powder, mp 131-134° C.

Sample No. 2 exhibits a log P of 1.924, and such a favorable log P valueindicates that the compound has the capability of passing theblood-brain barrier. The sample exhibits a Ki of 520 nM, indicating thatthe compound exhibits binding to certain CNS nicotinic receptors.

Sample No. 2 exhibits an EC₅₀ value of 27400 nM and an E_(max) value of76% for dopamine release, indicating that the compound inducesneurotransmitter release thereby exhibiting known nicotinicpharmacology. The sample exhibits an EC₅₀ value of 4390 nM and anE_(max) value of 32% in the rubidium ion flux assay, indicating that thecompound induces activation of CNS nicotinic receptors.

Sample No. 2 exhibits an E_(max) of 0% (at a concentration of 100 uM) atmuscle-type receptors, indicating that the compound does not induceactivation of muscle-type receptors. Sample No. 1 exhibits an E_(max) of36% (at a concentration of 100 uM) at ganglionic-type receptors. Thecompound has the capability to activate human CNS receptors withoutactivating muscle-type and ganglionic-type nicotinic acetylcholinereceptors to any significant degree. Thus, there is provided atherapeutic window for utilization in the treatment of CNS disorders.That is, at certain levels the compound shows CNS effects to asignificant degree but does not show undesirable muscle and ganglioneffects to any significant degree.

EXAMPLE 9

Sample No. 3 (2S)-(4E)-N-methyl-5-(3-pyridyl)-4-penten-2-aminehemigalactarate, which was prepared in accordance with the followingtechniques:

(2R)-4-Penten-2-ol

(2R)-4-Penten-2-ol was prepared in 82.5% yield from (R)-(+)-propyleneoxide according to procedures set forth in A. Kalivretenos, J. K.Stille, and L. S. Hegedus, J. Org. Chem. 56: 2883 (1991).

(2R)-(4E)-5-(3-Pyridyl)-4-penten-2-ol

A mixture of 3-bromopyridine (9.17 g, 58.04 mmol), (2R)-4-penten-2-ol(6.00 g, 69.65 mmol), palladium(II) acetate (130 mg, 0.58 mmol),tri-o-tolylphosphine (710 mg, 2.32 mmol), triethylamine (34.7 mL, 249.5mmol), and acetonitrile (35 mL) were heated in a sealed glass tube at140° C. for 14 h. The reaction mixture was cooled to ambienttemperature, diluted with water, and extracted with chloroform (3×200mL). The combined chloroform extracts were dried over sodium sulfate,filtered, and concentrated by rotary evaporation to give 6.17 g (65.2%)of a pale-yellow oil.

(2R)-(4E)-5-(3-Pyridyl)-4-penten-2-ol p-Toluenesulfonate

To a stirring solution of (2R)-(4E)-5-(3-pyridyl)-4-penten-2-ol (6.00 g,36.81 mmol) in dry pyridine (30 mL) at 0° C. was added p-toluenesulfonylchloride (21.05 g, 110.43 mmol). The reaction mixture was stirred for 24h at ambient temperature. The pyridine was removed by rotaryevaporation. Toluene (50 mL) was added to the residue and subsequentlyremoved by rotary evaporation. The crude product was stirred with asaturated solution of sodium bicarbonate (100 mL) and extracted withchloroform (3×100 mL). The combined chloroform extracts were dried oversodium sulfate, filtered, and concentrated by rotary evaporation to give11.67 g (84.0%) of a dark-brown, viscous oil.

(2S)-(4E)-N-Methyl-5-(3-pyridyl)-4-penten-2-amine

A mixture of (2R)-(4E)-5-(3-pyridyl)-4-penten-2-ol p-toluenesulfonate(9.00 g, 28.35 mmol), methylamine (200 mL, 40% solution in water), andethyl alcohol (10 mL) was stirred at ambient temperature for 18 h. Theresulting solution was extracted with chloroform (3×100 mL). Thecombined chloroform extracts were dried over sodium sulfate, filtered,and concentrated by rotary evaporation. The crude product was purifiedby column chromatography over aluminum oxide, eluting with ethylacetate-methanol (7:3, v/v). Selected fractions were combined andconcentrated by rotary evaporation, producing an oil. Furtherpurification by vacuum distillation furnished 1.20 g (24.0%) of acolorless oil, bp 90-100° C. at 0.5 mm Hg.

(2S)-(4E)-N-Methyl-5-(3-pyridyl)-4-penten-2-amine Hemigalactarate

(2S)-(4E)-N-Methyl-5-(3-pyridyl)-4-penten-2-amine (800 mg, 4.54 mmol)was dissolved in ethyl alcohol (20 mL), assisted by warming to 60° C.The warm solution was treated with galactaric acid (477 mg, 2.27 mmol)in one portion, followed by the dropwise addition of water (0.5 mL). Thesolution was filtered while hot to remove some insoluble material. Thefiltrate was allowed to cool to ambient temperature. The resultingcrystals were filtered, washed with anhydrous diethyl ether, and driedunder vacuum at 40° C. to yield 830 mg (65.4%) of an off-white,crystalline powder, mp 141-143° C.

Sample No. 3 exhibits a log P of 1.924, and such a favorable log P valueindicates that the compound has the capability of passing theblood-brain barrier. The sample exhibits a Ki of 34 nM. The low bindingconstant indicates that the compound exhibits good high affinity bindingto certain CNS nicotinic receptors.

Sample No. 3 exhibits an EC₅₀ value of 2600 nM and an E_(max) value of162% for dopamine release, indicating that the compound effectivelyinduces neurotransmitter release thereby exhibiting known nicotinicpharmacology. The sample exhibits an EC₅₀ value of 45 nM and an E_(max)value of 33% in the rubidium ion flux assay, indicating that thecompound effectively induces activation of CNS nicotinic receptors.

Sample No. 3 exhibits an E_(max) of 0% (at a concentration of 100 uM) atmuscle-type receptors, indicating that the compound does not induceactivation of muscle-type receptors. The sample exhibits an E_(max) of18% (at a concentration of 100 uM) at ganglionic-type receptors. Thecompound has the capability to activate human CNS receptors withoutactivating muscle-type and ganglionic-type nicotinic acetylcholinereceptors to any significant degree. Thus, there is provided atherapeutic window for utilization in the treatment of CNS disorders.That is, at certain levels the compound shows CNS effects to asignificant degree but does not show undesirable muscle or ganglioneffects to any significant degree.

EXAMPLE 10

Sample No. 4 is(4E)-N-methyl-5-(5-isopropoxy-3-pyridyl)-4-penten-2-aminehemigalactarate, which was prepared in accordance with the followingtechniques:

4-Penten-2-ol p-Toluenesulfonate

Under a nitrogen atmosphere, p-toluenesulfonyl chloride (16.92 g, 88.75mmol) was added to a cold (2° C.), stirring solution of 4-penten-2-ol(7.28 g, 84.52 mmol) in pyridine (60 mL). The solution was stirred at2-5° C. for 2 h and allowed to warm to ambient temperature over severalhours. The mixture, containing white solids, was poured into cold 3M HClsolution (250 mL) and extracted with CHCl₃ (4×75 mL). The combined CHCl₃extracts were washed with 3M HCl solution (4×100 mL), saturated NaClsolution (2×50 mL), dried (Na₂SO₄), filtered, concentrated on a rotaryevaporator, and further dried under high vacuum to afford 17.38 g(85.6%) of a light-amber oil.

N-Methyl-4-penten-2-amine

A glass pressure tube was charged with 4-penten-2-ol p-toluenesulfonate(17.30 g, 71.99 mmol) followed by a 40% solution of aqueous methylamine(111.85 g, 1.44 mol). The tube was sealed, and the mixture was stirredand heated at 122° C. for 16 h and allowed to cool to ambienttemperature. After further cooling to 0-5° C., the light-yellow solutionwas saturated with solid NaCl and extracted with diethyl ether (6×40 mL,inhibitor-free). The combined light-yellow ether extracts were dried(Na₂SO₄) and filtered. The ether was removed by distillation atatmospheric pressure using a 6-inch Vigreaux column and a short-pathdistillation apparatus. The residual light-yellow oil was distilled atatmospheric pressure collecting 3.72 g (52.1%) of a colorless oil, bp75-105° C.

N-Methyl-N-(tert-butoxycarbonyl)-4-penten-2-amine

Di-tert-butyl dicarbonate (6.84 g, 31.35 mmol) was quickly added inseveral portions to a cold (0-5° C.), stirring solution ofN-methyl-4-penten-2-amine (3.66 g, 25.68 mmol) in dry THF (25 mL,freshly distilled from sodium and benzophenone). The resultinglight-yellow solution was stirred and allowed to warm to ambienttemperature over several hours. The solution was concentrated on arotary evaporator. The resulting oil was vacuum distilled using ashort-path distillation apparatus, collecting 5.22 g (88.4%) of analmost colorless oil, bp 85-86° C. at 5.5 mm Hg.

5-Bromo-3-isopropoxypyridine can be prepared by two different methods(Method A and Method B) as described below.

5-Isopropoxy-3-bromopyridine (Method A)

Potassium metal (6.59 g, 168.84 mmol) was dissolved in dry 2-propanol(60.0 mL) under nitrogen. The resulting potassium isopropoxide washeated with 3,5-dibromopyridine (20.00 g, 84.42 mmol) and copper powder(1 g, 5% by weight of 3,5-dibromopyridine) at 140° C. in a sealed glasstube for 14 h. The reaction mixture was cooled to ambient temperatureand extracted with diethyl ether (4×200 mL). The combined ether extractswere dried over sodium sulfate, filtered, and concentrated by rotaryevaporation. The crude product obtained was purified by columnchromatography over aluminum oxide, eluting with ethyl acetate-hexane(1:9, v/v). Selected fractions were combined and concentrated by rotaryevaporation, producing a pale-yellow oil (12.99 g, 71.2%).

5-Isopropoxy-3-bromopyridine (Method B)

5-Bromonicotinamide

Under a nitrogen atmosphere, 5-bromonicotinic acid (10.10 g, 50.00 mmol)was dissolved in thionyl chloride (65.24 g, 0.55 mol), and the resultingsolution was stirred 45 min at ambient temperature. Excess thionylchloride was removed by distillation, and the residue was dried underhigh vacuum. The resulting solid was ground to a powder with a mortarand pestle under a nitrogen atmosphere and quickly added to a 28%solution of aqueous ammonia at 0° C. The mixture was stirred briefly at0° C. and then at ambient temperature for 3 h. The crude product wasfiltered, dried, and recrystallized from toluene-ethanol (1:1, v/v) togive 6.92 g (68.9%) of 5-bromonicotinamide, mp 210-213° C. (lit. mp219-219.5° C., see C. V. Greco et al., J. Heteocyclic Chem. 7(4): 761(1970)).

3-Amino-5-bromopyridine

Sodium hydroxide (2.50 g, 62.50 mmol) was added to a cold (0° C.),stirring suspension of calcium hypochlorite solution (1.53 g, 7.50 mmolof 70% solution) in water (35 mL). The mixture was stirred 15 min at 0°C. and filtered. The clarified filtrate was cooled and stirred in anice-salt bath while 5-bromonicotinamide (3.03 g, 15.1 mmol) was added inone portion. The suspension was stirred 2 h at 0° C., warmed to ambienttemperature, and heated on a steam bath for 1 h. After cooling, themixture was extracted with CHCl₃ (2×50 mL). The combined CHCl₃ extractswere dried (Na₂SO₄), filtered, and concentrated on a rotary evaporatorproducing 1.42 g of a light-yellow solid. The aqueous layer was adjustedto pH 8 with 6M HCl solution and extracted with CHCl₃ (2×50 mL). Thecombined CHCl₃ extracts were dried (Na₂SO₄), filtered, and concentratedon a rotary evaporator, affording 0.98 g of a brown solid. Based uponTLC analysis (toluene-ethanol (3:1, v/v)), both crude products werecombined to give 2.40 g which was dissolved in ethanol (10 mL) andfiltered to remove a small amount of a light-yellow solid (80 mg, mp225-227° C.). The filtrate was concentrated on a rotary evaporator, andthe residue was dissolved in 2-propanol (6 mL), filtered, and cooled to5° C. The resulting precipitate was filtered and dried to give a smallamount of a tan solid (65 mg, mp 63-64° C.). The filtrate wasconcentrated on a rotary evaporator, and the residue was dissolved intoluene (5 mL), assisted by heating, and cooled to 5° C. The resultingprecipitate was filtered and dried under vacuum to give 1.80 g of abrown, crystalline solid, mp 65-67° C. By concentrating the filtrate andcooling, a second crop of 0.27 g of a brown solid, mp 64-66° C. (lit. mp69-69.5° C., see C. V. Greco et al., J. Heteocyclic Chem. 7(4): 761(1970)) was obtained, bringing the total yield to 2.07 g (79.3%).

5-Isopropoxy-3-bromopyridine

A slurry of 5-amino-3-bromopyridine (1.29 g, 7.46 mmol) in 6M HClsolution (5 mL) was stirred 30 min at ambient temperature. The mixturewas concentrated under high vacuum, and the residue was vacuum dried for15 h at 50° C., affording a tan solid. The solid was slurried in2-propanol (25 mL), and treated with isoamyl nitrite (1.70 g, 15.00mmol). The mixture was stirred and heated under reflux for 1.5 h. Thesolution was concentrated by rotary evaporation, and the residue waspartitioned between diethyl ether and 1M NaOH solution. The aqueouslayer was separated and extracted with ether. The combined etherextracts were dried (Na₂SO₄), filtered, and concentrated by rotaryevaporation producing an orange oil (2.03 g). The oil was purified byvacuum distillation, collecting the fraction with bp 105-115° C. at 9 mmHg. The distilled product was further purified by column chromatographyon silica gel, eluting with 10-20% (v/v) diethyl ether in hexane.Selected fractions, based upon TLC analysis (R_(f) 0.40 in hexane-ether,(4:1, v/v)) were combined and concentrated by rotary evaporation to give566.0 mg (35.2%) of a clear, colorless oil.

(4E)-N-Methyl-N-(tert-butoxycarbonyl)-5-(5-isopropoxy-3-pyridyl)-4-penten-2-amine

Under a nitrogen atmosphere, a mixture of 5-isopropoxy-3-bromopyridine(847.0 mg, 3.92 mmol), N-methyl-N-(tert-butoxycarbonyl)-4-penten-2-amine(784.7 mg, 3.94 mmol), palladium(II) acetate (9.0 mg, 0.04 mmol),tri-o-tolylphosphine (50.0 mg, 0.16 mmol), triethylamine (0.73 g, 7.21mmol), and anhydrous acetonitrile (2 mL) was stirred and heated underreflux at 80° C. for 20 h. The mixture, containing solids was cooled,diluted with water (10 mL), and extracted with CHCl₃ (3×10 mL). Thecombined CHCl₃ extracts were dried (Na₂SO₄), filtered, and concentratedby rotary evaporation to give an oily residue (1.56 g). The crudeproduct was purified by column chromatography on silica gel, elutingwith 25-40% (v/v) ethyl acetate in hexane. Selected fractions containingthe product were combined and concentrated to give 1.15 g (87.8%) of alight-amber oil.

(4E)-N-Methyl-5-(5-isopropoxy-3-pyridyl)-4-penten-2-amine

Under a nitrogen atmosphere, a cold (0-5° C.), stirring solution of(4E)-N-methyl-N-(tert-butoxycarbonyl)-5-(5-isopropoxy-3-pyridyl)-4-penten-2-amine(150.0 mg, 0.45 mmol) in anisole (2.25 mL) was treated withtrifluoroacetic acid (1.49 g, 13.79 mmol) in one portion. The resultingsolution was stirred for 15 min at 0-5° C. TLC analysis on silica gel(EtOAc-hexane (3:1, v/v) and CH₃OH-Et₃N (97.5:2.5, v/v)) indicatedalmost complete reaction. After stirring for an additional 15 min, thesolution was concentrated on a rotary evaporator, followed by furtherdrying under vacuum at 0.5 mm Hg to give 278 mg of a dark-yellow oil.The oil was cooled (0-5° C.), basified with 10% NaOH solution (2 mL) topH 12, and saturated NaCl solution (5 mL) was added. The mixture wasextracted with CHCl₃ (5×3 mL). The combined CHCl₃ extracts were washedwith saturated NaCl solution (5 mL), dried (Na₂SO₄), filtered,concentrated by rotary evaporation, followed by further drying at 0.5 mmHg to give 104.7 mg of a light-yellow, slightly orange oil. The crudeproduct was purified by column chromatography on silica gel (20 g),eluting with CH₃OH-Et₃N (100:2, v/v). Selected fractions containing theproduct (R_(f) 0.37) were combined and concentrated on a rotaryevaporator to afford 72.3 mg of a yellow oil. The oil was dissolved inCHCl₃ (25 mL), and the CHCl₃ solution was dried (Na₂SO₄), filtered,concentrated by rotary evaporation, and vacuum dried to give 69.3 mg(66.2%) of a yellow oil.

(4E)-N-Methyl-5-(5-isopropoxy-3-pyridyl)-4-penten-2-amineHemigalactarate

(4E)-N-Methyl-5-(5-isopropoxy-3-pyridyl)-4-penten-2-amine (69.3 mg, 0.23mmol) was dissolved in CH₃OH (1.5 mL), assisted by heating. The warmsolution was treated with galactaric acid (24.3 mg, 0.12 mmol), followedby water (0.3 mL). The resulting solution was warmed and filteredthrough glass wool to remove a few insoluble particles, washing thefilter plug with 0.4 mL of a CH₃OH—H₂O (4:1, v/v) solution. The filtratewas diluted with CH₃OH (1.5 mL), and the light-yellow solution wasstored at 5° C. for 15 h. No precipitate had formed; therefore, thesolution was concentrated on a rotary evaporator. The resulting solidswere triturated with anhydrous diethyl ether (3×6 mL). The product wasdried under a stream of nitrogen, dried under high vacuum, followed byfurther vacuum drying at 45° C. for 15 h to afford 73.0 mg (93.1%) of anoff-white powder, mp 144-146.5° C.

Sample No. 4 exhibits a log P of 2.957, and such a favorable log P valueindicates that the compound has the capability of passing theblood-brain barrier. The sample exhibits a Ki of 10 nM. The low bindingconstant indicates that the compound exhibits good high affinity bindingto certain CNS nicotinic receptors.

Sample No. 4 exhibits an EC₅₀ value of 100 nM and an E_(max) value of57% for dopamine release, indicating that the compound effectivelyinduces neurotransmitter release thereby exhibiting known nicotinicpharmacology. The sample exhibits an EC₅₀ value of 100 nM and an E_(max)value of 60% in the rubidium ion flux assay, indicating that thecompound effectively induces activation of CNS nicotinic receptors.

Sample No. 4 exhibits an E_(max) of 15% (at a concentration of 100 uM)at muscle-type receptors, indicating that the compound does notsignificantly induce activation of muscle-type receptors. The sampleexhibits an E_(max) of 36% (at a concentration of 100 uM) atganglionic-type receptors. The compound has the capability to activatehuman CNS receptors without activating muscle-type and ganglionic-typenicotinic acetylcholine receptors to any significant degree. Thus, thereis provided a therapeutic window for utilization in the treatment of CNSdisorders. That is, at certain levels the compound shows CNS effects toa significant degree but does not show undesirable muscle and ganglioneffects to any significant degree. The compound begins to cause muscleeffects and ganglion effects only when employed in amounts greater thanthose required to activate rubidium ion flux and dopamine release, thusindicating a lack of undesirable side effects in subjects receivingadministration of this compound.

EXAMPLE 11

Sample No. 5 is(2R)-(4E)-N-methyl-5-(5-isopropoxy-3-pyridyl)-4-penten-2-aminehemigalactarate, which was prepared in accordance with the followingtechniques:

(2S)-4-Penten-2-ol

(2S)-4-Penten-2-ol was prepared from (S)-(−)-propylene oxide using aprocedure similar to that described for the preparation of(2R)-4-penten-2-ol from (R)-(+)-propylene oxide as detailed in A.Kalivretenos, J. K. Stille, and L. S. Hegedus, J. Org. Chem. 56: 2883(1991). Thus, a 1.0M solution of vinylmagnesium bromide in THF (129 mL,129.0 mmol) was slowly added to a suspension of copper(I) iodide (2.46g, 12.92 mmol) in dry THF (40 mL, distilled from sodium andbenzophenone) at −25° C. After stirring 5 min, a solution of(S)-(−)-propylene oxide (5.00 g, 86.1 mmol) in dry THF (5 mL) was added.The mixture was allowed to warm to −10° C. and placed in a freezer at 0°C. for 12 h. The mixture was stirred for an additional 1 h at 0° C. andpoured into a mixture of saturated ammonium chloride solution (100 mL)and ice (100 g). The mixture was stirred for 4 h and extracted withether (3×100 mL). The combined ether extracts were dried (K₂CO₃),filtered, and concentrated under reduced pressure by rotary evaporationat 0° C. The resulting brown oil was vacuum distilled to yield 5.86 g(79.1%) of a colorless distillate, bp 37-39° C. at 9 mm Hg.

(2S)-(4E)-5-(5-Isopropoxy-3-pyridyl)-4-penten-2-ol

A mixture of 5-isopropoxy-3-bromopyridine (12.56 g, 58.13 mmol),(2S)-4-penten-2-ol (5.00 g, 58.05 mmol), palladium(II) acetate (130 mg,0.58 mmol), tri-o-tolylphosphine (706 mg, 2.32 mmol), triethylamine (35mL, 252 mmol) and acetonitrile (35 mL) were heated in a sealed glasstube at 130-140° C. for 8 h. The reaction mixture was cooled to ambienttemperature. The solvent was removed under reduced pressure on a rotaryevaporator. Water (50 mL) was added and the mixture was extracted withchloroform (3×50 mL). The combined chloroform extracts were dried(K₂CO₃), filtered, and concentrated by rotary evaporation. The crudeproduct was purified by column chromatography over silica gel, elutingwith chloroform-acetone (95:5, v/v). Selected fractions were combinedand concentrated by rotary evaporation, producing 7.80 g (60.7%) of apale-yellow oil.

(2S)-(4E)-5-(5-Isopropoxy-3-pyridyl)-4-penten-2-ol p-Toluenesulfonate

Under a nitrogen atmosphere, p-toluenesulfonyl chloride (11.45 g, 60.06mmol) was added to a stirring solution of(2S)-(4E)-5-(5-isopropoxy-3-pyridyl)-4-penten-2-ol (7.00 g, 31.63 mmol)in dry triethylamine (30 mL) at 0° C. After stirring and warming toambient temperature over 18 h, the mixture was concentrated on a rotaryevaporator. The crude product was stirred with saturated NaHCO₃ solution(100 mL) for 1 hour and extracted with chloroform (3×50 mL). Thecombined chloroform extracts were dried (K₂CO₃), filtered, andconcentrated by rotary evaporation to afford 10.00 g (84.2%) as adark-brown oil, which was used without further purification.

(2R)-(4E)-N-Methyl-5-(5-isopropoxy-3-pyridyl)-4-penten-2-amine

A mixture of (2S)-(4E)-5-(5-isopropoxy-3-pyridyl)-4-penten-2-olp-toluenesulfonate (10.00 g, 26.63 mmol) and methylamine (50 mL, 2.0Msolution in THF) was heated at 100° C. for 10 h in a sealed glass tube.The mixture was cooled to ambient temperature and concentrated underreduced pressure on a rotary evaporator. The crude product was treatedwith saturated NaHCO₃ solution (50 mL) and extracted with chloroform(4×50 mL). The combined chloroform extracts were dried (K₂CO₃),filtered, and concentrated by rotary evaporation to afford a dark-brownoil (3.50 g). The crude product was purified by repeated (twice) columnchromatography on silica gel, eluting with chloroform-methanol (95:5,v/v). Selected fractions were combined, concentrated by rotaryevaporation affording a light-brown oil (2.50 g). The oil was furtherpurified by vacuum distillation using a short-path distillationapparatus, collecting 2.05 g (32.9%) of a colorless oil, bp 98-100° C.at 0.04 mm Hg.

(2R)-(4E)-N-Methyl-5-(5-isopropoxy-3-pyridyl)-4-penten-2-amineHemigalactarate

Galactaric acid (314.0 mg, 1.49 mmol) was dissolved in 2-propanol (10mL) and water (˜1 mL), assisted by heating and sonicating over a periodof 10 min. A solution of(2R)-(4E)-N-methyl-5-(5-isopropoxy-3-pyridyl)-4-penten-2-amine (700.3mg, 2.99 mmol) in 2-propanol (10 mL) was then added, followed byadditional sonicating and heating at 60° C. for 10 min. The hot solutionwas filtered to remove some insoluble material. The solvent was removedon a rotary evaporator; the resulting light-brown syrup was dissolved indry 2-propanol (5 mL) and cooled at 4° C. The resulting precipitate wasfiltered and dried under high vacuum to yield 657 mg (64.8%) of anoff-white, crystalline powder, mp 150-153° C.

Sample No. 5 exhibits a log P of 2.957, and such a favorable log P valueindicates that the compound has the capability of passing theblood-brain barrier. The sample exhibits a Ki of 62 nM. The low bindingconstant indicates that the compound exhibits good high affinity bindingto certain CNS nicotinic receptors.

Sample No. 5 exhibits an EC₅₀ value of 634 nM and an E_(max) value of38% for dopamine release, indicating that the compound effectivelyinduces neurotransmitter release thereby exhibiting known nicotinicpharmacology. The sample exhibits an EC₅₀ value of 88 nM and an E_(max)value of 14% in the rubidium ion flux assay, indicating that thecompound induces activation of CNS nicotinic receptors.

Sample No. 5 exhibits an E_(max) of 0% (at a concentration of 100 uM) atmuscle-type receptors, indicating that the compound does not induceactivation of muscle-type receptors. The sample exhibits an E_(max) of14% (at a concentration of 100 uM) at ganglionic-type receptors. Thecompound has the capability to activate human CNS receptors withoutactivating muscle-type and ganglionic-type nicotinic acetylcholinereceptors to any significant degree. Thus, there is provided atherapeutic window for utilization in the treatment of CNS disorders.That is, at certain levels the compound shows CNS effects to asignificant degree but does not show undesirable muscle and gangliaeffects to any significant degree.

EXAMPLE 12

Sample No. 6 is(2S)-(4E)-N-methyl-5-(5-isopropoxy-3-pyridyl)-4-penten-2-aminehemigalactarate, which was prepared in accordance with the followingtechniques:

(2R)-4-Penten-2-ol

(2R)-4-Penten-2-ol was prepared in 82.5% yield from (R)-(+)-propyleneoxide according to procedures set forth in A. Kalivretenos, J. K.Stille, and L. S. Hegedus, J. Org. Chem. 56: 2883 (1991).

(2R)-(4E)-5-(5-Isopropoxy-3-pyridyl)-4-penten-2-ol

A mixture of 5-isopropoxy-3-bromopyridine (10.26 g, 47.50 mmol),(2R)-4-penten-2-ol (4.91 g, 57.00 mmol), palladium(II) acetate (106 mg,0.47 mmol), tri-o-tolylphosphine (578 mg, 1.90 mmol), triethylamine(28.46 mL, 204.25 mmol), and acetonitrile (30 mL) were heated in asealed glass tube at 140° C. for 14 h. The reaction mixture was cooledto ambient temperature, diluted with water, and extracted withchloroform (3×200 mL). The combined chloroform extracts were dried oversodium sulfate, filtered, and concentrated by rotary evaporation to givea pale-yellow oil (8.92 g, 85.0%).

(2R)-(4E)-5-(5-Isopropoxy-3-pyridyl)-4-penten-2-ol p-Toluenesulfonate

To a stirred solution of(2R)-(4E)-5-(5-isopropoxy-3-pyridyl)-4-penten-2-ol (8.50 g, 38.46 mmol)in dry pyridine (30 mL) at 0° C. was added p-toluenesulfonyl chloride(14.67 g, 76.92 mmol). The reaction mixture was stirred for 24 h atambient temperature. The pyridine was removed by rotary evaporation.Toluene (50 mL) was added to the residue and removed by rotaryevaporation. The crude product was stirred with a saturated solution ofsodium bicarbonate (100 mL) and extracted with chloroform (3×100 mL).The combined chloroform extracts were dried over sodium sulfate,filtered, and concentrated by rotary evaporation to yield a dark-brown,viscous oil (11.75 g, 81.5%).

(2S)-(4E)-N-Methyl-5-(5-isopropoxy-3-pyridyl)-4-penten-2-amine

A mixture of (2R)-(4E)-5-(5-isopropoxy-3-pyridyl)-4-penten-2-olp-toluenesulfonate (11.00 g, 29.33 mmol), methylamine (200 mL, 40%solution in water), and ethyl alcohol (10 mL) was stirred at ambienttemperature for 18 h. The resulting solution was extracted withchloroform (3×100 mL). The combined chloroform extracts were dried oversodium sulfate, filtered, and concentrated by rotary evaporation. Thecrude product was purified by column chromatography over aluminum oxide,eluting with ethyl acetate-methanol (7:3, v/v). Selected fractions werecombined and concentrated by rotary evaporation, producing an oil.Further purification by vacuum distillation furnished 2.10 g (31.0%) ofa colorless oil, bp 90-100° C. at 0.5 mm Hg.

(2S)-(4E)-N-Methyl-5-(5-isopropoxy-3-pyridyl)-4-penten-2-amineHemigalactarate

(2S)-(4E)-N-Methyl-5-(5-isopropoxy-3-pyridyl)-4-penten-2-amine (2.00 g,8.55 mmol) was dissolved in ethyl alcohol (20 mL), assisted by warmingto 70° C. The warm solution was treated with galactaric acid (900 mg,4.27 mmol) in one portion, followed by the dropwise addition of water(0.5 mL). The solution was filtered while hot to remove some insolublematerial. The filtrate was allowed to cool to ambient temperature. Theresulting crystals were filtered, washed with anhydrous diethyl ether,and dried under vacuum at 40° C. to yield a white, crystalline powder(750 mg, 26.0%), mp 140-143° C.

Sample No. 6 exhibits a log P of 2.957, and such a favorable log P valueindicates that the compound has the capability of passing theblood-brain barrier. The sample exhibits a Ki of 11 nM. The low bindingconstant indicates that the compound exhibits good high affinity bindingto certain CNS nicotinic receptors.

Sample No. 6 exhibits an EC₅₀ value of 106 nM and an E_(max) value of85% for dopamine release, indicating that the compound effectivelyinduces neurotransmitter release thereby exhibiting known nicotinicpharmacology. The sample exhibits an EC₅₀ value of 220 nM and an E_(max)value of 58% in the rubidium ion flux assay, indicating that thecompound effectively induces activation of CNS nicotinic receptors.

Sample No. 6 exhibits an E_(max) of 0% (at a concentration of 100 uM) atmuscle-type receptors, indicating that the compound does not induceactivation of muscle-type receptors. The sample exhibits an E_(max) of0% (at a concentration of 100 uM) at ganglionic-type receptors. Thecompound has the capability to activate human CNS receptors withoutactivating muscle-type and ganglionic-type nicotinic acetylcholinereceptors to any significant degree. Thus, there is provided atherapeutic window for utilization in the treatment of CNS disorders.That is, at certain levels the compound shows CNS effects to asignificant degree but does not show undesirable muscle or gangliaeffects to any significant degree.

EXAMPLE 13

Sample No. 7 is (4E)-N-methyl-5-(5-bromo-3-pyridyl)-4-penten-2-amine,which was prepared in accordance with the following techniques:

(4E)-5-(5-Bromo-3-pyridyl)-4-penten-2-ol

A mixture of 3,5-dibromopyridine (23.60 g, 100.0 mmol), 4-penten-2-ol(10.8 g, 125.0 mmol), palladium(II) acetate (230 mg, 1.02 mmol),tri-o-tolylphosphine (1.20 g, 3.94 mmol), triethylamine (29.7 mL, 213.45mmol), and acetonitrile (40 mL) were heated in a sealed glass tube at140° C. for 14 h. The reaction mixture was cooled to ambienttemperature, diluted with water, and extracted with chloroform (3×200mL). The combined chloroform extracts were dried over sodium sulfate andfiltered. Removal of solvent by rotary evaporation, followed by columnchromatography over silica gel eluting with acetone-chloroform (1:9,v/v) furnished 8.10 g (34.0%) of a pale-yellow oil.

(4E)-N-Methyl-5-(5-bromo-3-pyridyl)-4-penten-2-amine

To a stirring solution of (4E)-5-(5-bromo-3-pyridyl)-4-penten-2-ol (3.14g, 13.0 mmol) in dry pyridine (30 mL) at 0° C. was addedp-toluenesulfonyl chloride (3.71 g, 19.5 mmol). The reaction mixture wasstirred for 24 h at ambient temperature. The pyridine was removed byrotary evaporation. Toluene (50 mL) was added to the residue andsubsequently removed by rotary evaporation. The crude product wasstirred with a saturated solution of sodium bicarbonate (100 mL) andextracted with chloroform (3×100 mL). The combined chloroform extractswere dried over sodium sulfate, filtered, and concentrated by rotaryevaporation to give (4E)-5-(5-bromo-3-pyridyl)-4-penten-2-olp-toluenesulfonate. The resulting tosylate was treated with excessmethylamine (40% solution in water), ethyl alcohol (10 mL), and stirredat ambient temperature for 18 h. The resulting solution was extractedwith chloroform (3×100 mL). The combined chloroform extracts were driedover sodium sulfate and filtered. Removal of solvent by rotaryevaporation followed by column chromatography over silica gel elutingwith chloroform-methanol (95:5, v/v) produced 1.50 g (45.0%) of apale-yellow oil.

Sample No. 7 exhibits a log P of 2.026, and such a favorable log P valueindicates that the compound has the capability of passing theblood-brain barrier. The sample exhibits a Ki of 284 nM, indicating thatthe compound exhibits binding to certain CNS nicotinic receptors.

Sample No. 7 exhibits an EC₅₀ value of 202 nM and an E_(max) value of18% for dopamine release, indicating that the compound inducesneurotransmitter release thereby exhibiting known nicotinicpharmacology. The sample exhibits an E_(max) value of 0% in the rubidiumion flux assay, indicating that the compound exhibits selective effectsat certain CNS nicotinic receptors.

Sample No. 7 exhibits an E_(max) of 6% (at a concentration of 100 uM) atmuscle-type receptors, indicating that the compound does not induceactivation of muscle-type receptors. The sample exhibits an E_(max) of8% (at a concentration of 100 uM) at ganglionic-type receptors. Thecompound has the capability to activate human CNS receptors withoutactivating muscle-type and ganglionic-type nicotinic acetylcholinereceptors to any significant degree. Thus, there is provided atherapeutic window for utilization in the treatment of CNS disorders.That is, at certain levels the compound shows CNS effects to asignificant degree but does not show undesirable muscle or gangliaeffects to any significant degree.

EXAMPLE 14

Sample No. 8 is (4E)-N-methyl-5-(5-methoxy-3-pyridyl)-4-penten-2-aminehemigalactarate, which was prepared in accordance with the followingtechniques:

5-Methoxy-3-bromopyridine

A mixture of 3,5-dibromopyridine (20.00 g, 84.42 mmol), sodium methoxide(11.40 g, 211.06 mmol), and copper powder (1 g, 5% by weight of3,5-dibromopyridine) in dry methanol was heated in a sealed glass tubeat 150° C. for 14 h. The reaction mixture was cooled to ambienttemperature and extracted with diethyl ether (4×200 mL). The combinedether extracts were dried over sodium sulfate, filtered, andconcentrated by rotary evaporation. The crude product was purified bycolumn chromatography over aluminum oxide, eluting with ethylacetate-hexane (1:9, v/v). Selected fractions were combined andconcentrated by rotary evaporation, producing 9.40 g (59.5%) of acolorless oil, which tended to crystallize upon cooling.

(4E)-5-(5-Methoxy-3-pyridyl)-4-penten-2-ol

A mixture of 5-methoxy-3-bromopyridine (4.11 g, 21.86 mmol),4-penten-2-ol (2.25 g, 26.23 mmol), palladium(II) acetate (49 mg, 0.22mmol), tri-o-tolylphosphine (266 mg, 0.87 mmol), triethylamine (13.71mL, 98.37 mmol), and acetonitrile (15 mL) were heated in a sealed glasstube at 140° C. for 14 h. The reaction mixture was cooled to ambienttemperature, diluted with water, and extracted with chloroform (3×200mL). The combined chloroform extracts were dried over sodium sulfate,filtered, and concentrated by rotary evaporation to give 3.53 g (70.3%)of a pale-yellow oil.

(4E)-5-(5-Methoxy-3-pyridyl)-4-penten-2-ol p-Toluenesulfonate

To a stirred solution of (4E)-5-(5-methoxy-3-pyridyl)-4-penten-2-ol(3.50 g, 18.13 mmol) in dry pyridine (15 mL) at 0° C. was addedp-toluenesulfonyl chloride (6.91 g, 36.27 mmol). The reaction mixturewas stirred for 24 h at ambient temperature. The pyridine was removed byrotary evaporation. Toluene (50 mL) was added to the residue andsubsequently removed by rotary evaporation. The crude product wasstirred with a saturated solution of sodium bicarbonate (100 mL) andextracted with chloroform (3×100 mL). The combined chloroform extractswere dried over sodium sulfate, filtered, and concentrated by rotaryevaporation to give 5.25 g (83.5%) of a dark-brown, viscous oil.

(4E)-N-Methyl-5-(5-methoxy-3-pyridyl)-4-penten-2-amine

A mixture of (4E)-5-(5-methoxy-3-pyridyl)-4-penten-2-olp-toluenesulfonate (5.00 g, 14.41 mmol), methylamine (150 mL, 40%solution in water), and ethyl alcohol (10 mL) was stirred at ambienttemperature for 18 h. The resulting solution was extracted withchloroform (3×100 mL). The combined chloroform extracts were dried oversodium sulfate, filtered, and concentrated by rotary evaporation. Thecrude product was purified by column chromatography over aluminum oxide,eluting with ethyl acetate-methanol (7:3, v/v). Selected fractions werecombined and concentrated by rotary evaporation, producing an oil.Further purification by vacuum distillation furnished 1.25 g (41.8%) ofa colorless oil, bp 90-100° C. at 0.5 mm Hg.

(4E)-N-Methyl-5-(5-methoxy-3-pyridyl)-4-penten-2-amine Hemigalactarate

(4E)-N-Methyl-5-(5-methoxy-3-pyridyl)-4-penten-2-amine (1.20 g, 5.83mmol) was dissolved in ethyl alcohol (20 mL), assisted by warming to 60°C. The warm solution was treated with galactaric acid (610 mg, 2.91mmol) in one portion, followed by dropwise addition of water (0.5 mL).The solution was filtered while hot to remove some insoluble material.The filtrate was allowed to cool to ambient temperature. The resultingcrystals were filtered, washed with anhydrous diethyl ether, and driedunder vacuum at 40° C. to yield 1.05 g (58.0%) of a white, crystallinepowder, mp 143-145° C.

Sample No. 8 exhibits a log P of 2.025, and such a favorable log P valueindicates that the compound has the capability of passing theblood-brain barrier. The sample exhibits a Ki of 22 nM. The low bindingconstant indicates that the compound exhibits good high affinity bindingto certain CNS nicotinic receptors.

Sample No. 8 exhibits an EC₅₀ value of 5000 nM and an E_(max) value of110% for dopamine release, indicating that the compound effectivelyinduces neurotransmitter release thereby exhibiting known nicotinicpharmacology.

Sample No. 8 exhibits an E_(max) of 10% (at a concentration of 100 uM)at muscle-type receptors, indicating that the compound does not induceactivation of muscle-type receptors. The sample exhibits an E_(max) of2% (at a concentration of 100 uM) at ganglionic-type receptors. Thecompound has the capability to activate human CNS receptors withoutactivating muscle-type and ganglionic-type nicotinic acetylcholinereceptors to any significant degree. Thus, there is provided atherapeutic window for utilization in the treatment of CNS disorders.That is, at certain levels the compound shows CNS effects to asignificant degree but do not show undesirable muscle or ganglioneffects to any significant degree.

EXAMPLE 15

Sample No. 9 is(4E)-N-methyl-5-(5-ethoxy-3-pyridyl)-4-penten-2-aminehemigalactarate,which was prepared in accordance with the following techniques:

5-Ethoxy-3-bromopyridine

Under a nitrogen atmosphere, sodium (4.60 g, 200.0 mmol) was added toabsolute ethanol (100 mL) at 0-5° C., and the stirring mixture wasallowed to warm to ambient temperature over 18 h. To the resultingsolution was added 3,5-dibromopyridine (31.50 g, 133.0 mmol), followedby DMF (100 mL). The mixture was heated at 70° C. for 48 h. The brownmixture was cooled, poured into water (600 mL), and extracted with ether(3×500 mL). The combined ether extracts were dried (Na₂SO₄), filtered,and concentrated by rotary evaporation, producing 46.70 g of an oil.Purification by vacuum distillation afforded 22.85 g (85.0%) of an oil,bp 89-90° C. at 2.8 mm Hg, (lit. bp 111° C. at 5 mm Hg, see K. Clarke etal., J. Chem. Soc. 1885 (1960)).

(4E)-N-Methyl-N-(tert-butoxycarbonyl)-5-(5-ethoxy-3-pyridyl)-4-penten-2-amine

Under a nitrogen atmosphere, a mixture of 5-ethoxy-3-bromopyridine (1.20g, 5.94 mmol), N-methyl-N-(tert-butoxycarbonyl)-4-penten-2-amine (1.18g, 5.94 mmol), palladium(II) acetate (13.5 mg, 0.06 mmol),tri-o-tolylphosphine (73.1 mg, 0.24 mmol), triethylamine (1.5 mL, 10.8mmol), and anhydrous acetonitrile (3 mL) was stirred and heated underreflux at 80-85° C. for 28 h. The resulting mixture, containing beigesolids, was cooled to ambient temperature, diluted with water (20 mL),and extracted with CHCl₃ (3×20 mL). The combined light-yellow CHCl₃extracts were dried (Na₂SO₄), filtered, concentrated by rotaryevaporation, and vacuum dried producing a yellow oil (1.69 g). The crudeproduct was purified by column chromatography on silica gel (100 g),eluting with ethyl acetate-hexane (1:1, v/v). Selected fractionscontaining the product (R_(f) 0.20) were combined, concentrated byrotary evaporation, and the residue was vacuum dried to give 0.67 g(35.2%) of a light-yellow oil.

(4E)-N-Methyl-5-(5-ethoxy-3-pyridyl)-4-penten-2-amine

Under a nitrogen atmosphere, a cold (0-5° C.), stirring solution of(4E)-N-methyl-N-(tert-butoxycarbonyl)-5-(5-ethoxy-3-pyridyl)-4-penten-2-amine(0.67 g, 2.09 mmol) in anisole (10 mL) was treated dropwise over 30 minwith trifluoroacetic acid (10.40 g, 91.17 mmol). The resulting solutionwas stirred for 45 min at 0-5° C. and was then concentrated by rotaryevaporation. The light-yellow oil was further dried under high vacuum at0.5 mm Hg. The resulting oil was cooled (0-5° C.), basified with 10%NaOH solution (10 mL), treated with saturated NaCl solution (7.5 mL),and extracted with CHCl₃ (4×10 mL). The combined light-yellow CHCl₃extracts were washed with saturated NaCl solution (20 mL), dried(Na₂SO₄), filtered, concentrated by rotary evaporation, followed byfurther drying at 0.5 mm Hg producing a brown oil (0.46 g). The crudeproduct was purified by column chromatography on silica gel (56 g),eluting with CH₃OH-Et₃N (98:2, v/v). Selected fractions containing theproduct (R_(f) 0.35) were combined and concentrated on a rotaryevaporator. The residue was dissolved in CHCl₃, and the CHCl₃ solutionwas dried (Na₂SO₄), filtered, concentrated by rotary evaporation, andvacuum dried to give 327.5 mg (71.0%) of a light-yellow oil.

(4E)-N-Methyl-5-(5-ethoxy-3-pyridyl)-4-penten-2-amine Hemigalactarate

To a solution of (4E)-N-methyl-5-(5-ethoxy-3-pyridyl)-4-penten-2-amine(151.4 mg, 0.68 mmol) in absolute ethanol (2.3 mL) was added galactaricacid (72.2 mg, 0.34 mmol). Water (0.5 mL) was added dropwise whilegently warming the light-brown solution. The solution was filteredthrough glass wool to remove a few insoluble particles, washing thefilter plug with ethanol-water (4:1, v/v) (1 mL). The filtrate wasdiluted with ethanol (3.4 mL), cooled to ambient temperature, andfurther cooled at 5° C. for 18 h. Because no precipitate had formed, thesolution was concentrated on a rotary evaporator. The resulting solidswere dried under high vacuum and recrystallized from 2-propanol-water.After cooling at 5° C. for 48 h the product was filtered, washed withcold 2-propanol, and vacuum dried at 45° C. for 6 h. Further vacuumdrying at ambient temperature for 18 h afforded 168 mg (76.1%) of awhite to off-white powder, mp 141-143.5° C.

Sample No. 9 exhibits a log P of 2.556, and such a favorable log P valueindicates that the compound has the capability of passing theblood-brain barrier. The sample exhibits a Ki of 15 nM. The low bindingconstant indicates that the compound exhibits good high affinity bindingto certain CNS nicotinic receptors.

Sample No. 9 exhibits an EC₅₀ value of 520 nM and an E_(max) value of85% for dopamine release, indicating that the compound effectivelyinduces neurotransmitter release thereby exhibiting known nicotinicpharmacology. The sample exhibits an E_(max) value of 0% in the rubidiumion flux assay, indicating that the compound exhibits selective effectsat certain CNS nicotinic receptors.

Sample No. 9 exhibits an E_(max) of 21% (at a concentration of 100 uM)at muscle-type receptors, indicating that the compound does not induceactivation of muscle-type receptors. The sample exhibits an E_(max) of9% (at a concentration of 100 uM) at ganglionic-type receptors. Thecompound has the capability to activate human CNS receptors withoutactivating muscle-type and ganglionic-type nicotinic acetylcholinereceptors to any significant degree. Thus, there is provided atherapeutic window for utilization in the treatment of CNS disorders.That is, at certain levels the compound shows CNS effects to asignificant degree but does not show undesirable muscle or gangliaeffects to any significant degree.

EXAMPLE 16

Sample No. 10 is(4E)-N-methyl-5-(6-amino-5-methyl-3-pyridyl)-4-penten-2-amine, which wasprepared in accordance with the following techniques:

(4E)-N-Methyl-N-(tert-butoxycarbonyl)-5-(6-amino-5-methyl-3-pyridyl)-4-penten-2-amine

A mixture of 2-amino-5-bromo-3-methylpyridine (1.41 g, 7.53 mmol),N-methyl-N-(tert-butoxycarbonyl)-4-penten-2-amine (1.50 g, 7.53 mmol),palladium(II) acetate (33.8 mg, 0.15 mmol), tri-o-tolylphosphine (183.2mg, 0.60 mmol), triethylamine (4.50 mL, 32.3 mmol), and anhydrousacetonitrile (8 mL) was stirred and heated at 130-132° C. in a sealedglass tube for 18 h. The mixture was further heated at 140° C. for 84 h.The resulting dark-brown solution was cooled to ambient temperature andconcentrated by rotary evaporation. The residue was diluted with water(25 mL) and extracted with CH₂Cl₂ (3×25 mL). The combined CH₂Cl₂extracts were dried (Na₂SO₄), filtered, concentrated by rotaryevaporation, and vacuum dried producing a dark-brown oil (2.84 g). Thecrude product was purified by column chromatography on silica gel (135g), eluting with ethyl acetate-hexane (3:1, v/v) to remove impurities,followed by elution with CH₃OH-Et₃N (98:2, v/v) to collect the product.Fractions containing the product (R_(f) 0.70) were combined anddissolved in CHCl₃. The CHCl₃ solution was dried (Na₂SO₄), filtered,concentrated by rotary evaporation, and vacuum dried to give 1.11 g(48.4%) of an amber-brown oil.

(4E)-N-Methyl-5-(6-amino-5-methyl-3-pyridyl)-4-penten-2-amine

Under a nitrogen atmosphere, trifluoroacetic acid (17.76 g, 155.76 mmol)was added dropwise, via addition funnel, over 30 min to a cold (0-5°C.), stirring solution of(4E)-N-methyl-N-(tert-butoxycarbonyl)-5-(6-amino-5-methyl-3-pyridyl)-4-penten-2-amine(1.11 g, 3.47 mmol) in anisole (15 mL). The resulting solution wasstirred for 45 min at 0-5° C. and was then concentrated by rotaryevaporation. The viscous, brown oil was further dried under high vacuumfor 18 h. The crude product was cooled (0-5° C.), basified with 10% NaOHsolution (10 mL), treated with saturated NaCl solution (10 mL), andextracted with CHCl₃ (5×10 mL). The combined CHCl₃ extracts were dried(Na₂SO₄), filtered, concentrated by rotary evaporation, followed byfurther drying under high vacuum yielding a dark-brown oil. The crudeproduct was purified by column chromatography on silica gel (50 g),eluting with CHCl₃—CH₃OH-Et₃N (4:1:1, v/v/v). Selected fractionscontaining the product (R_(f) 0.13) were combined and concentrated byrotary evaporation, and the residue was re-chromatographed on silica gel(50 g) eluting with CHCl₃—CH₃OH (7:3, v/v). Fractions containing theproduct (R_(f) 0.12) were combined and concentrated by rotaryevaporation. The residue was dissolved in CHCl₃, and the CHCl₃ solutionwas dried (Na₂SO₄), filtered, concentrated by rotary evaporation, andvacuum dried affording a yellow oil (0.087 g) which tended tocrystallize. The semi-crystalline material was dissolved in a warmsolution of hexane containing a small amount of ethyl acetate. The warmsolution was decanted from an insoluble gum. The solution was allowed tocool to ambient temperature and was further cooled at 5° C. for 18 h.The resulting crystalline solids were collected, washed with hexane, andvacuum dried at 40° C. for 16 h. The yield was 30.8 mg (4.3%) of alight-yellow powder, mp 78-81° C.

Sample No. 10 exhibits a log P of 1.333, and such a favorable log Pvalue indicates that the compound has the capability of passing theblood-brain barrier. The sample exhibits a Ki of 720 nM. The bindingconstant indicates that the compound exhibits high affinity binding tocertain CNS nicotinic receptors.

Sample No. 10 exhibits an EC₅₀ value of 100000 nM and an E_(max) valueof 200% for dopamine release, indicating that the compound inducesneurotransmitter release thereby exhibiting known nicotinicpharmacology.

Sample No. 10 exhibits an E_(max) of 0% (at a concentration of 100 uM)at muscle-type receptors, indicating that the compound does not induceactivation of muscle-type receptors. The sample exhibits an E_(max) of0% (at a concentration of 100 uM) at ganglionic-type receptors. Thecompound has the capability to activate human CNS receptors withoutactivating muscle-type and ganglionic-type nicotinic acetylcholinereceptors to any significant degree. Thus, there is provided atherapeutic window for utilization in the treatment of CNS disorders.

EXAMPLE 17

Sample No. 11 is (4E)-N-methyl-5-(5-pyrimidinyl)-4-penten-2-aminehemigalactarate, which was prepared in accordance with the followingtechniques:

(4E)-N-Methyl-N-(tert-butoxycarbonyl)-5-(5-pyrimidinyl)-4-penten-2-ol

A glass pressure tube was charged with a mixture of 5-bromopyrimidine(1.28 g, 8.05 mmol), N-methyl-N-(tert-butoxycarbonyl)-4-penten-2-amine(1.60 g, 8.05 mmol), palladium(II) acetate (18.1 mg, 0.08 mmol),tri-o-tolylphosphine (98.6 mg, 0.32 mmol), triethylamine (3.00 mL, 21.5mmol), and anhydrous acetonitrile (6 mL). The tube was flushed withnitrogen and sealed. The mixture was stirred and heated at 90° C. for 64h, followed by further heating at 110° C. for 24 h. The resulting brownmixture was cooled to ambient temperature and concentrated by rotaryevaporation. The brown residue was diluted with water (25 mL) andextracted with CH₂Cl₂ (3×25 mL). The combined CH₂Cl₂ extracts were dried(Na₂SO₄), filtered, concentrated by rotary evaporation, and vacuum driedproducing a dark-brown oil (2.24 g). The crude product was purified bycolumn chromatography on silica gel (120 g), eluting with ethylacetate-hexane (3:1, v/v). Fractions containing the product (R_(f) 0.21)were combined, concentrated by rotary evaporation, and vacuum dried togive 1.05 g (46.9%) of a light-yellow oil.

(4E)-N-Methyl-5-(5-pyrimidinyl)-4-penten-2-ol

Under a nitrogen atmosphere, a stirring solution of(4E)-N-methyl-N-(tert-butoxycarbonyl)-5-(5-pyrimidinyl)-4-penten-2-ol(881.2 mg, 3.18 mmol) in CHCl₃ (55 mL) was treated dropwise at ambienttemperature with iodotrimethylsilane (1.41 g, 7.03 mmol). The resultingsolution was stirred for 30 min. Methanol (55 mL) was added, and thesolution was stirred for an additional 1 h and was concentrated byrotary evaporation. With ice-bath cooling, the residue was basified with10% NaOH solution (10 mL), treated with saturated NaCl solution (10 mL),and extracted with CHCl₃ (8×10 mL). The combined CHCl₃ extracts weredried (Na₂SO₄), filtered, concentrated by rotary evaporation, followedby further drying under high vacuum producing a light-brown oil (0.50g). The crude product was purified by column chromatography on silicagel (50 g), eluting with CH₃OH—NH₄OH (20:1, v/v). Fractions containingthe product (R_(f) 0.43) were combined, concentrated by rotaryevaporation, and the residue was dissolved in CHCl₃. The CHCl₃ solutionwas dried (Na₂SO₄), filtered, concentrated by rotary evaporation, andvacuum dried affording 306.4 mg (54.4%) of a light-amber oil.

(4E)-N-Methyl-5-(5-pyrimidinyl)-4-penten-2-amine Hemigalactarate

To a warm solution of (4E)-N-methyl-5-(5-pyrimidinyl)-4-penten-2-amine(258.6 mg, 1.46 mmol) in absolute ethanol (2.3 mL) was added galactaricacid (153.3 mg, 0.73 mmol). Water (0.8 mL) was added, and the solutionwas heated to near reflux until most of the solids dissolved. Thesolution was filtered through glass wool to remove a few white,insoluble particles, washing the filter plug with a warm solution ofethanol-water (4:1, v/v) (1.1 mL). The filtrate was diluted with ethanol(6.5 mL), cooled to ambient temperature, and further cooled at 5° C. for48 h. The white precipitate was filtered, washed with cold ethanol, andvacuum dried at 40° C. for 18 h. The yield was 390.6 mg (94.8%) of afluffy, white, crystalline powder, mp 164-167° C.

Sample No. 11 is determined to exhibit a log P of 0.571, and such afavorable log P value indicates that the compound has the capability ofpassing the blood-brain barrier. The sample exhibits a Ki of 179 nM. Thelow binding constant indicates that the compound exhibits good highaffinity binding to certain CNS nicotinic receptors.

Sample No. 11 exhibits an EC₅₀ value of 1500 nM and an E_(max) value of80% for dopamine release, indicating that the compound effectivelyinduces neurotransmitter release thereby exhibiting known nicotinicpharmacology. The sample exhibits an EC₅₀ value of 100000 nM and anE_(max) value of 0% in the rubidium ion flux assay, indicating that thecompound exhibits selective effects at certain CNS nicotinic receptors.

Sample No. 11 exhibits an E_(max) of 0% (at a concentration of 100 uM)at muscle-type receptors, indicating that the compound does not induceactivation of muscle-type receptors. The sample exhibits an E_(max) of13% (at a concentration of 100 uM) at ganglionic-type receptors. Thecompound has the capability to activate human CNS receptors withoutactivating muscle-type and ganglionic-type nicotinic acetylcholinereceptors to any significant degree. Thus, there is provided atherapeutic window for utilization in the treatment of CNS disorders.

EXAMPLE 18

Sample 12 is (4E)-N-methyl-5-(1-oxo-3-pyridyl)-4-penten-2-amine, whichwas prepared in accordance with the following techniques:

(4E)-N-Methyl-N-(tert-butoxycarbonyl)-5-(3-pyridyl)-4-penten-2-amine

A solution of (4E)-N-methyl-5-(3-pyridyl)-4-penten-2-amine (140.6 mg,0.798 mmol) in dry THF (7 mL, freshly distilled from sodium andbenzophenone) was cooled to 0° C. and treated with di-tert-butyldicarbonate (191.5 mg, 0.878 mmol) under a nitrogen atmosphere. Theresulting mixture was stirred and allowed to warm to ambient temperatureover 16 h. The solution was concentrated by rotary evaporation and driedunder high vacuum for 1 h producing a yellow oil (226.1 mg). The crudeproduct was purified by column chromatography on silica gel (20 g, Merck70-230 mesh) eluting with CHCl₃—CH₃OH (95:5, v/v). Selected fractions,containing the product (R_(f) 0.48), were combined, concentrated byrotary evaporation, and vacuum dried briefly at 1 mm Hg to give 217.9 mg(98.8%) of a yellow oil.

(4E)-N-Methyl-N-(tert-butoxycarbonyl)-5-(1-oxo-3-pyridyl)-4-penten-2-amine

An ice-cold (0° C.) solution of(4E)-N-methyl-N-(tert-butoxycarbonyl)-5-(3-pyridyl)-4-penten-2-amine(216.7 mg, 0.784 mmol) in CH₂Cl₂ (5 mL) was treated with(3-chloroperoxybenzoic acid) (154.7 mg, 0.511-0.771 mmol) (57-86%purity) in one portion. After stirring for 30 min at 0° C., TLC analysisindicated an incomplete reaction (R_(f) 0.5 for the Boc-protected amine,R_(f) 0.08-0.15 for the Boc-protected amine N-oxide), and additional3-chloroperoxybenzoic acid (64.7 mg, 0.214-0.322 mmol) was added. Afterstorage at 5° C. for 16 h, the solution was treated with 1 M NaOHsolution (10 mL) and 10% NaHSO₃ solution (2 mL). The CH₂Cl₂ phase wasseparated; the aqueous phase was extracted with CH₂Cl₂ (2×5 mL). AllCH₂Cl₂ extracts were combined, dried (Na₂SO₄), filtered, concentrated byrotary evaporation, and vacuum dried briefly at 1.5 mm Hg to give 221.6mg (96.7%) of a yellow oil.

(4E)-N-Methyl-5-(1-oxo-3-pyridyl)-4-penten-2-amine

Under a nitrogen atmosphere, a cold (0° C.), stirring solution of(4E)-N-methyl-N-(tert-butoxycarbonyl)-5-(1-oxo-3-pyridyl)-4-penten-2-amine(215.9 mg, 0.738 mmol) in anisole (2.5 mL) was treated drop-wise withtrifluoroacetic acid (2.5 mL, 32.5 mmol) over 3 min. The resultinglight-yellow solution was allowed to stir for 45 min at 0-5° C. and wasthen concentrated by rotary evaporation using a 70° C. water bath. Theresulting liquid was vacuum dried at 0.5 mm Hg for 16 h to produce alight-yellow oil (302.5 mg). The oil was basified at 0-5° C. with 1 MNaOH solution (2 mL), followed by treatment with saturated NaCl solution(2 mL). The mixture was extracted with CHCl₃ (14×5 mL). The combinedCHCl₃ extracts were dried (Na₂SO₄), filtered, concentrated by rotaryevaporation, and vacuum dried to give 143.8 mg (quantitative yield) of abrown, syrupy semi-solid (R_(f) 0.23 in CH₃OH-Et₃N (97:3, v/v)).

Sample No. 12 exhibits a Ki of 5900 nM. The binding constant indicatesthat the compound exhibits binding to certain CNS nicotinic receptors.The sample exhibits a neurotransmitter release E_(max) value of 9%.

Sample No. 12 exhibits an E_(max) of 0% (at a concentration of 100 uM)at muscle-type receptors, indicating that the compound does not induceactivation of muscle-type receptors. The sample exhibits an E_(max) of8% (at a concentration of 100 uM) at ganglionic-type receptors. Thecompound has the capability to activate human CNS receptors withoutactivating muscle-type and ganglionic-type nicotinic acetylcholinereceptors to any significant degree. Thus, there is provided atherapeutic window for utilization in the treatment of CNS disorders.That is, at certain levels the compound shows CNS effects to asignificant degree but do not show undesirable muscle or ganglioneffects to any significant degree.

EXAMPLE 19

Sample No. 13 is (4E)-5-(5-isopropoxy-3-pyridyl)-4-penten-2-aminehemigalactarate, which was prepared in accordance with the followingtechniques:

N-(1-Penten-4-yl)phthalimide

To a stirred solution of 4-penten-2-ol (5.00 g, 58.1 mmol), phthalimide(8.55 g, 58.1 mmol), and triphenylphosphine (15.2 g, 58.1 mmol) in THF(40 mL), at 0° C. under nitrogen, was added a solution of diethylazodicarboxylate (10.1 g, 58.1 mmol) in THF (20 mL) dropwise. Themixture was stirred at 0° C. (12 h) and then at 25° C. (12 h). Themixture was diluted with water and extracted three times withchloroform. The chloroform extracts were dried (Na₂SO₄), evaporated andcolumn chromatographed on Merck silica gel 60 (70-230 mesh) withchloroform to give 8.77 g (70.2% yield) of colorless oil.

(4E)-N-Phthaloyl-5-(5-isopropoxy-3-pyridyl)-4-penten-2-amine

A mixture of palladium(II) acetate (2.2 mg, 0.010 mmol),tri-o-tolylphosphine (12 mg, 0.040 mmol), 3-bromo-5-isopropoxypyridine(216 mg, 1.00 mmol), and N-(4-(1-penten)yl)phthalimide (215 mg, 1.00mmol) was diluted with acetonitrile (1.0 mL) and triethylamine (0.5 mL)and heated (80° C. oil bath) under nitrogen for 25 h. The mixture wascooled, poured into water (5 mL) and extracted with chloroform (3×5 mL).The extracts were dried (Na₂SO₄), evaporated and column chromatographedon 15 g of Merck silica gel 60 (70-230 mesh) with 1:1:3 (v/v) ethylacetate/chloroform/hexane to give 268 mg (76.6% yield) of very viscous,light yellow oil.

(4E)-5-(5-Isopropoxy-3-pyridyl)-4-penten-2-amine

(4E)-N-Phthaloyl-5-(5-isopropoxy-3-pyridyl)-4-penten-2-amine (258 mg,0.736 mmol) was dissolved in methanol (4 mL) and treated with hydrazinehydrate (0.15 mL, 3.1 mmol) and stirred under nitrogen at 25° C. for 36h. The reaction mixture was then poured into a mixture of 1 M NaOHsolution (15 mL) and saturated NaCl solution (15 mL) and extracted withbenzene (3×15 mL). The benzene extracts were dried (Na₂SO₄), evaporatedand column chromatographed on 7 g of Merck silica gel 60 (70-230 mesh)with 5-10% (v/v) methanol, 2.5% (v/v) triethylamine in benzene. Thisprovided 118 mg (72.8% yield) of light yellow oil.

(4E)-5-(5-Isopropoxy-3-pyridyl)-4-penten-2-amine Hemigalactarate

(4E)-5-(5-Isopropoxy-3-pyridyl)-4-penten-2-amine (112 mg, 0.508 mmol)was dissolved in methanol (2.5 mL) and treated with galactaric acid (53mg, 0.25 mmol) and water (0.20 mL). The mixture was warmed slightly,filtered through a glass wool plug and cooled slowly to 0° C., at whichtemperature it remained for 48 h. Vacuum filtration and vacuum ovendrying (40° C., 24 h) gave 53 mg of white solid (mp 171.5-173.5° C.).Second and third crops of 50 mg and 5 mg (mp 170-173° C. and 169-172° C.respectively) were isolated by concentrating the supernatant, bringingthe total yield to 108 mg (65.5% yield). The three salt samples wereslurried together in hot 100% ethanol, cooled, and filtered to give ananalytical sample of 27 mg of fine, white powder, mp 170-172° C.

Sample No. 13 exhibits a Ki of 413 nM. The binding constant indicatesthat the compound exhibits binding to certain CNS nicotinic receptors.

Sample No. 13 exhibits an E_(max) of 13% (at a concentration of 100 uM)at muscle-type receptors. The sample exhibits an E_(max) of 5% (at aconcentration of 100 uM) at ganglionic-type receptors. The sampleexhibits a neurotransmitter E_(max) of 32%.

EXAMPLE 20

Sample No. 14 is (4E)-N-methyl-5-(6-hydroxy-3-pyridyl)-4-penten-2-amineoxalate, which was prepared in accordance with the following techniques:

(4E)-N-Methyl-N-(tert-butoxycarbonyl)-5-(6-methoxy-3-pyridyl)-4-penten-2-amine

A 185 mL Ace-Glass pressure tube was charged with5-bromo-2-methoxypyridine (2.80 g, 14.9 mmol),N-methyl-N-(tert-butoxycarbonyl)-4-penten-2-amine (2.97 g, 14.9 mmol),prepared as previously described, palladium(II) acetate (33.4 mg, 0.149mmol), tri-o-tolylphosphine (181 mg, 0.596 mmol), triethylamine (5 mL)and acetonitrile (10 mL). The tube was flushed with nitrogen, sealed,and the mixture was stirred and heated at 95° C. (oil bath temperature)for 18 h. The tube contents were cooled; more palladium(II) acetate(33.4 mg, 0.149 mmol) and tri-o-tolylphosphine (181 mg, 0.596 mmol) wereadded. The mixture was further stirred and heated at 94° C. for 20 h.TLC analysis (hexane-ethyl acetate (2:1)) indicated the presence of5-bromo-2-methoxypyridine. Therefore, more palladium(II) acetate (33.4mg, 0.149 mmol) and tri-o-tolylphosphine (181 mg, 0.596 mmol) wereadded, and the mixture was heated at 95° C. for an additional 20 h. Themixture was cooled and concentrated via rotary evaporator. The residuewas diluted with water (35 mL) and extracted with dichloromethane (50mL, 2×35 mL). The combined dichloromethane extracts were dried (Na₂SO₄),filtered, and concentrated under vacuum to produce a light-brown, oilysemisolid (5.61 g). The crude product was purified by columnchromatography on silica gel (70-230 mesh) (200 g) eluting with ahexane-ethyl acetate gradient (64:1→6:1). Fractions containing theproduct (R_(f) 0.28 in hexane-ethyl acetate (6:1)) were combined andconcentrated under vacuum to give 2.36 g of an oily, yellow semisolid.Impure fractions were combined and concentrated to give 1.48 g of alight-yellow oil. This material was re-chromatographed on the silica gel(70-230 mesh) (95 g) eluting with the previously described hexane-ethylacetate gradient (64:1→6:1). All fractions containing the product werecombined and concentrated under vacuum to give 0.85 g of a light-yellowoil, bringing the total yield to 2.915 (63.9%).

(4E)-N-Methyl-5-(6-methoxy-3-pyridyl)-4-penten-2-amine

Under a nitrogen atmosphere, a cold (0-5° C.), stirring solution of(4E)-N-methyl-N-(tert-butoxycarbonyl)-5-(6-methoxy-3-pyridyl)-4-penten-2-amine(2.90 g, 9.45 mmol) in dichloromethane (20 mL) was treated drop-wiseover 15 min with trifluoroacetic acid (15 mL). After stirring for 30min, the solution was concentrated to a yellow-orange oil. The residuewas diluted with saturated aqueous NaCl solution (15 mL), cooled to 0-5°C., and basified with 10% aqueous NaOH solution (22 mL). The mixture wasextracted with CHCl₃ (5×25 mL). The combined CHCl₃ extracts were dried(Na₂SO₄), filtered, and concentrated under vacuum to give a light-yellowoil (1.88 g). The crude product was purified by column chromatography onsilica gel (70-230 mesh) (150 g), eluting with a CH₃OH—NH₄OH step-wisegradient (100:1→15:1 in increments of 25:1). Fractions containing theproduct (R_(f) 0.28 in CHCl₃—CH₃OH-Et₃N (50:1:1)) were kept separatefrom those containing an impurity (R_(f) 0.35) and were combined andconcentrated to give 0.76 g of a light-yellow oil. Impure fractions werecombined and concentrated to give 1.20 g of light-yellow oil. The lattermaterial was re-chromatographed on a new silica gel column (75 g) usingthe same CH₃OH—NH₄OH gradient elution protocol. Impure fractions werecombined and concentrated to give 1.08 g of light-yellow oil. The lattermaterial was re-chromatographed (6 times) on a new silica gel columns(45 g and 25 g) using CHCl₃—CH₃OH-Et₃N step-wise gradient (16:1→1:1 inCHCl₃—CH₃OH, with each gradient step containing 1% Et₃N). All fractionscontaining the product were combined and concentrated under vacuum togive 1.368 g (70.2%) of a light-yellow oil.

(4E)-N-Methyl-5-(6-hydroxy-3-pyridyl)-4-penten-2-amine

(4E)-N-Methyl-5-(6-methoxy-3-pyridyl)-4-penten-2-amine (0.385 g, 1.86mmol) was dissolved in 48% HBr (30 mL), and the solution was heated atvigorous reflux (120-130° C.) for 17 h. The reaction mixture wasconcentrated by rotary evaporation to ˜5 mL volume and then neutralizedwith saturated aqueous NaHCO₃. The mixture was evaporated, leaving 1.49g of a mixture of salts and the desired product. This was placed on asilica gel column (32 g), which was eluted with 50:1 methanol/aqueousammonia. Concentration of selected fractions gave 0.264 g of light brownviscous oil. GCMS analysis indicated that the sample was 91% desiredmaterial (67% corrected yield).

(4E)-N-Methyl-5-(6-hydroxy-3-pyridyl)-4-penten-2-amine oxalate

(4E)-N-Methyl-5-(6-hydroxy-3-pyridyl)-4-penten-2-amine (0.263 g of 91%,1.23 mmol) was dissolved in warm absolute ethanol (3 mL) and combinedwith oxalic acid (0.110 g, 1.23 mmol) in warm absolute ethanol (4.5 mL).The solution was cooled at 4° C. for 1 h, during which time an oilymaterial was deposited. The ethanol was evaporated to leave a dark brownoil, which was combined with 2-propanol (3 mL). This mixture(heterogeneous) was refluxed as absolute ethanol was added drop-wise.Once homogeneous, the mixture was cooled to ambient temperature as thewalls of the flask were scratched with a spatula. A tan precipitateformed. The mixture was kept at 4° C. overnight and filtered. The filtercake was washed with cold 2-propanol and vacuum dried (40° C.) for 48 h.The resulting tan powder weighed 0.248 g (71% yield), mp 174-175.5° C.

Sample No. 14 exhibits a Ki of 32.5 μM.

EXAMPLE 21

Sample No. 15 is (4E)-5-(5-pyrimidinyl)-4-penten-2-amine hydrochloride,which was prepared in accordance with the following scheme:

(R)-Propylene oxide was reacted with vinyl magnesium chloride to form(S)-pent-1-ene-4-oxide (as the magnesium chloride salt), which wastosylated (tosyl=p-toluene sulfonyl) to form the tosylated intermediate(S)-pent-1-ene-4-ol tosylate. The tosylate group was then displaced withphthalimide. The resulting phthalimidated intermediate was reacted with5-bromopyrimidine in the presence of a palladium catalyst in a Heck-typecoupling reaction. The phthalimide protecting group was then removed byreaction with hydrazine and hydrochloric acid to yield the free amine asthe hydrochloride salt.

Each of the publications and patents described herein is herebyincorporated by reference for all purposes. The foregoing isillustrative of the present invention and is not to be construed aslimiting thereof. The invention is defined by the following claims, withequivalents of the claims to be included therein.

1. A compound of the formula:

wherein X is selected from the group consisting of C—H, C—F, C—Cl, C—Br,C—I, C—R′, C—NR′R″, C—CF₃, C—CN, C—NO₂, C—C₂R′, C—, C—SCH₃, C—N₃,C—SO₂CH₃, C—OR′, C—SR′, C—C(═O)NR′R″, C—NR′C(═O)R′, C—C(═O)R′,C—C(═O)OR′, C(CH₂)_(q)OR′, C—OC(═O)R′, COC(═O)NR′R″ and C—NR′C(═O)OR′,X′ is N or NO, q is an integer from 1 to 6; each A, A″ and A′″individually is a substituent selected from the group consisting of H,F, Cl, Br, I, R′, —NR′R″, —CF₃, —OH, —CN, —NO₂, —C₂R′, —SH, —SCH₃, —N₃,—SO₂CH₃, —OR′, —SR′, —C(═O)NR′R″, —NR′C(═O)R′, —C(═O)R′, —C(═O)OR′,—(CH₂)_(q)OR′, —OC(═O)R′, —OC(═O)NR′R″ and —NR′C(═O)OR′, m and n areintegers such that the sum of m and n is an integer from 1 to 8 and n isat least 1; E^(VI) is C₁₋₁₀ alkyl; each Z′ and Z″ individually ishydrogen, lower alkyl, —C(═O)R′, —C(═O)OR′, —C(═O)NR′R″, —C(═S)R′,—C(═S)OR′, —C(═S)NR′R″, —C(═NR′)R′, —C(═NR′)OR′, or —C(═NR′)NR′R″; andR′ and R″ are, individually, hydrogen, C₁-C₁₀ alkyl, an aromaticgroup-containing species or a substituted aromatic group-containingspecies, or R′ and R″ form a cycloalkyl group, wherein the aromaticgroup-containing species is pyridyl, quinolinyl, pyrimidinyl, phenyl, orbenzyl and the substituents are as defined above with respect to A, A′,and A″ or pharmaceutically acceptable salt thereof.
 2. The compound ofclaim 1, wherein A′, A″, and A′″ are hydrogen.
 3. The compound of claim1, wherein E^(VI) is CH₃.
 4. The compound of claim 1, wherein Z′ is CH₃.5. The compound of claim 1, wherein Z″ is —C(═O)CH₃, —C(═O)N(CH₃)₂,—C(═S)CH₂CH₃, —C(═S)NH₂, —C(═S)N(CH₃)₂, —C(═S)OCH₃, or —C(═O)C₆H₅. 6.The compound of claim 1, wherein Z′ or Z″ is selected from the groupconsisting of hydrogen, lower alkyl, —C(═O)R′, —C(═O)OR′, —C(═O)NR′R″,—C(═NR′)R′, —C(═NR′)OR′, and —C(═NR′)NR′R″.
 7. The compound of claim 1,wherein Z″ is —C(═O)OR′, wherein R′ is hydrogen, lower alkyl or aryl. 8.The compound of claim 1, wherein Z′ is H and Z″ is CH₃.
 9. A urea,thiourea, carbamate, thiocarbamate, amide or thioamide, form of acompound selected from the group consisting of(4E)-N-methyl-5-(3-pyridyl)-4-penten-2-amine,(4E)-N-methyl-5-(5-methoxy-3-pyridyl)-4-penten-2-amine,(4E)-N-methyl-5-(6-amino-5-methyl-3-pyridyl)-4-penten-2-amine,(2R)-(4E)-N-methyl-5-(3-pyridyl)-4-penten-2-amine,(2R)-(4E)-N-methyl-5-(5-isopropoxy-3-pyridyl)-4-penten-2-amine,(4E)-N-methyl-5-(5-bromo-3-pyridyl)-4-penten-2-amine,(4E)-N-methyl-5-(5-ethoxy-3-pyridyl)-4-penten-2-amine, or(2S)-(4E)-N-methyl-5-(3-pyridyl)-4-penten-2-amine,(4E)-N-methyl-5-(5-isopropoxy-3-pyridyl)-4-penten-2-amine, and(2S)-(4E)-N-methyl-5-(5-isopropoxy-3-pyridyl)-4-penten-2-amine andpharmaceutically acceptable salts thereof.
 10. A compound selected fromthe group consisting of N-oxide forms of(4E)-N-methyl-5-(3-pyridyl)-4-penten-2-amine,(4E)-N-methyl-5-(5-methoxy-3-pyridyl)-4-penten-2-amine,(4E)-N-methyl-5-(6-amino-5-methyl-3-pyridyl)-4-penten-2-amine,(2R)-(4E)-N-methyl-5-(3-pyridyl)-4-penten-2-amine,(2R)-(4E)-N-methyl-5-(5-isopropoxy-3-pyridyl)-4-penten-2-amine,(4E)-N-methyl-5-(5-bromo-3-pyridyl)-4-penten-2-amine,(4E)-N-methyl-5-(5-ethoxy-3-pyridyl)-4-penten-2-amine, or(2S)-(4E)-N-methyl-5-(3-pyridyl)-4-penten-2-amine,(4E)-N-methyl-5-(5-isopropoxy-3-pyridyl)-4-penten-2-amine, and(2S)-(4E)-N-methyl-5-(5-isopropoxy-3-pyridyl)-4-penten-2-amine andpharmaceutically acceptable salts thereof.
 11. A compound selected fromthe group consisting of 2-hydroxy, 4-hydroxy, 6-hydroxy, 2,4-dihydroxy,2,6-dihydroxy, and 4,6-dihydroxy forms of(4E)-N-methyl-5-(3-pyridyl)-4-penten-2-amine,(4E)-N-methyl-5-(5-methoxy-3-pyridyl)-4-penten-2-amine,(4E)-N-methyl-5-(6-amino-5-methyl-3-pyridyl)-4-penten-2-amine,(2R)-(4E)-N-methyl-5-(3-pyridyl)-4-penten-2-amine,(2R)-(4E)-N-methyl-5-(5-isopropoxy-3-pyridyl)-4-penten-2-amine,(4E)-N-methyl-5-(5-bromo-3-pyridyl)-4-penten-2-amine,(4E)-N-methyl-5-(5-ethoxy-3-pyridyl)-4-penten-2-amine, or(2S)-(4E)-N-methyl-5-(3-pyridyl)-4-penten-2-amine,(4E)-N-methyl-5-(5-isopropoxy-3-pyridyl)-4-penten-2-amine, and(2S)-(4E)-N-methyl-5-(5-isopropoxy-3-pyridyl)-4-penten-2-amine and saltsthereof.
 12. A compound selected from the group consisting of(4E)-N-methyl-5-(4-hydroxy-3-pyridyl)-4-penten-2-amine,(4E)-N-methyl-5-(4-hydroxy-5-methoxy-3-pyridyl)-4-penten-2-amine, (4E)-N-methyl-5-(6-amino-4-hydroxy-5-methyl-3-pyridyl)-4-penten-2-amine,(2R)-(4E)-N-methyl-5-(4-hydroxy-3-pyridyl)-4-penten-2-amine,(2R)-(4E)-N-methyl-5-(4-hydroxy-5-isopropoxy-3-pyridyl)-4-penten-2-amine,(4E)-N-methyl-5-(4-hydroxy-5-bromo-3-pyridyl)-4-penten-2-amine,(4E)-N-methyl-5-(4-hydroxy-5-ethoxy-3-pyridyl)-4-penten-2-amine, or(2S)-(4E)-N-methyl-5-(4-hydroxy-3-pyridyl)-4-penten-2-amine,(4E)-N-methyl-5-(4-hydroxy-5-isopropoxy-3-pyridyl)-4-penten-2-amine, and(2S)-(4E)-N-methyl-5-(4-hydroxy-5-isopropoxy-3-pyridyl)-4-penten-2-amineand pharmaceutically acceptable salts thereof.
 13. A compound selectedfrom the group consisting of(4E)-5-(4-hydroxy-3-pyridyl)-4-penten-2-amine,(4E)-N-5-(4-hydroxy-5-methoxy-3-pyridyl)-4-penten-2-amine,(4E)-5-(6-amino-4-hydroxy-5-methyl-3-pyridyl)-4-penten-2-amine,(2R)-(4E)-5-(4-hydroxy-3-pyridyl)-4-penten-2-amine,(2R)-(4E)-5-(4-hydroxy-5-isopropoxy-3-pyridyl)-4-penten-2-amine,(4E)-5-(4-hydroxy-5-bromo-3-pyridyl)-4-penten-2-amine,(4E)-5-(4-hydroxy-5-ethoxy-3-pyridyl)-4-penten-2-amine,(2S)-(4E)-5-(4-hydroxy-3-pyridyl)-4-penten-2-amine,(4E)-5-(4-hydroxy-5-isopropoxy-3-pyridyl)-4-penten-2-amine, and(2S)-(4E)-5-(4-hydroxy-5-isopropoxy-3-pyridyl)-4-penten-2-amine andpharmaceutically acceptable salts thereof.
 14. A compound selected fromthe group consisting of xy-3-pyridyl)-4-penten-2-amine,(4E)-N-5-(4-hydroxy-5-methoxy-3-pyridyl)-4-penten-2-amine,(4E)-5-(6-amino-4-hydroxy-5-methyl-3-pyridyl)-4-penten-2-amine,(2R)-(4E)-5-(4-hydroxy-3-pyridyl)-4-penten-2-amine,(2R)-(4E)-5-(4-hydroxy-5-isopropoxy-3-pyridyl)-4-penten-2-amine,(4E)-5-(4-hydroxy-5-bromo-3-pyridyl)-4-penten-2-amine,(4E)-5-(4-hydroxy-5-ethoxy-3-pyridyl)-4-penten-2-amine,(2S)-(4E)-5-(4-hydroxy-3-pyridyl)-4-penten-2-amine,(4E)-5-(4-hydroxy-5-isopropoxy-3-pyridyl)-4-penten-2-amine, and(2S)-(4E)-5-(4-hydroxy-5-isopropoxy-3-pyridyl)-4-penten-2-amine andpharmaceutically acceptable salts thereof.(2S)-(4E)-N-methyl-5-(5-methoxy-3-pyridyl)-4-penten-2-amine.
 15. Acompound selected from the group consisting of(2S)-(4E)-N-methyl-5-(5-cyclohexyloxy-3-pyridyl)-4-penten-2-amine,(2R)-(4E)-N-methyl-5-(5-cyclohexyloxy-3-pyridyl)-4-penten-2-amine,(2S)-(4E)-N-methyl-5-(5-phenoxy-3-pyridyl)-4-penten-2-amine,(2R)-(4E)-N-methyl-5-(5-phenoxy-3-pyridyl)-4-penten-2-amine,(2S)-(4E)-N-methyl-5-(5-(4-fluorophenoxy)-3-pyridyl)-4-penten-2-amine,(2R)-(4E)-N-methyl-5-(5-(4-fluorophenoxy)-3-pyridyl)-4-penten-2-amine,(2S)-(4E)-N-methyl-5-(5-(4-chlorophenoxy)-3-pyridyl)-4-penten-2-amine,(2R)-(4E)-N-methyl-5-(5-(4-chlorophenoxy)-3-pyridyl)-4-penten-2-amine,(2S)-(4E)-N-methyl-5-(5-(3-cyanophenoxy)-3-pyridyl)-4-penten-2-amine,(2R)-(4E)-N-methyl-5-(5-(3-cyanophenoxy)-3-pyridyl)-4-penten-2-amine,(2S)-(4E)-N-methyl-5-(5-(5-indolyloxy)-3-pyridyl)-4-penten-2-amine,(2R)-(4E)-N-methyl-5-(5-(5-indolyloxy)-3-pyridyl)-4-penten-2-amine andmixtures thereof.
 16. A pharmaceutical composition comprising a compoundof claim 1 or a pharmaceutically acceptable salt thereof and apharmaceutically acceptable carrier.
 17. A method for preparing an arylsubstituted olefinic amine comprising: condensing an olefinic alcoholwith an aromatic halide using a palladium catalyst and converting thecondensation product to an aryl substituted olefinic amine.
 18. A methodfor preparing an aryl substituted olefinic amine comprising a)condensing an olefinic amine with an aromatic halide using a palladiumcatalyst, wherein the amine group is protected with a protecting group,and b) deprotecting the amine group.
 19. The method of claim 18, furthercomprising: c) converting the aryl substituted olefinic amine to ahemigalactarate salt.
 20. The method of claim 19, wherein the olefinicamine is reacted with approximately 0.5 equivalents of galactaric acid.21. The method of claim 18, wherein the aromatic halide is selected from3-halopyridines.
 22. The method of claim 17 further comprisingprotecting the olefinic alcohol prior to condensing.
 23. The method ofclaim 17, wherein converting transforming the alcohol group into aleaving group and displacing the leaving group with an amine selectedfrom ammonia, a primary amine and a secondary amine.
 24. The method ofclaim 23, wherein transforming of the alcohol group comprising reactingthe alcohol group with methanesulfonyl chloride or p-toluenesulfonylchloride.
 25. The method of claim 23 wherein the amine is ammonia anddisplacement produces an aryl substituted olefinic primary aminecompound.
 26. The method of claim 23, wherein the amine is a primaryamine and displacement produces an aryl substituted olefinic secondaryamine compound.
 27. The method of claim 23, wherein the amine is asecondary amine and displacement produces an aryl substituted olefinictertiary amine compound.
 28. The method of claim 17, wherein theolefinic alcohol is selected from 4-penten-1-ol, 4-penten-2-ol,5-hexen-2-ol, 5-hexen-3-ol, 3-methyl-3-buten-1-ol,2-methyl-3-buten-1-ol, 4-methyl-4-penten-1-ol, 4-methyl-4-penten-2-ol,1-octen-4-ol, 5-methyl-1-hepten-4-ol, 4-methyl-5-hexen-2-ol,5-methyl-5-hexen-2-ol, 5-hexen-2-ol and 5-methyl-5-hexen-3-ol.
 29. Themethod of claim 17, wherein at least one of the olefinic alcohol, thecondensation product and the aryl substituted olefinic amine isoptically active.
 30. The method of claim 18, wherein at least one ofthe olefinic amine and the aryl substituted olefinic amine is opticallyactive.
 31. A method for preparing aryl substituted olefinic aminescomprising condensing an allylic alcohol with an aromatic halide to forman aryl substituted olefinic aldehyde, and subjecting the aldehyde toreductive amination to form an aryl substituted olefinic amine.
 32. Themethod of claim 31, wherein the aromatic halide is selected from3-halopyridines.
 33. An alcohol condensation product prepared byreacting an olefinic alcohol with an aromatic halide.
 34. An arylsubstituted olefinic amine prepared by converting the alcoholcondensation product of claim 33 to an amine.
 35. A condensation productprepared by reacting an olefinic amine with an aromatic halide, whereinthe amine group is protected.
 36. An aryl substituted olefinic amineprepared by deprotecting the amine group of the condensation product ofclaim
 35. 37. A hemigalactarate salt prepared by reacting an arylsubstituted olefinic amine of claim 34 with approximately 0.5equivalents of galactaric acid.